Heteroaryl sulfonamides and CCR2/CCR9

ABSTRACT

Compounds are provided that act as potent antagonists of the CCR2 receptor. Animal testing demonstrates that these compounds are useful for treating inflammation, a hallmark disease for CCR2. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR2-mediated diseases, and as controls in assays for the identification of CCR2 antagonists.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/383,788, filed Dec. 19, 2016, which is a divisional of U.S.application Ser. No. 13/938,119, filed Jul. 9, 2013, which is acontinuation of U.S. application Ser. No. 12/309,314, filed Feb. 1,2011, now U.S. Pat. No. 8,519,135, which issued Aug. 27, 2013, which isa 371 national phase of PCT/US2007/015893, filed Jul. 12, 2007, which isa continuation-in-part of U.S. application Ser. No. 11/486,974, filedJul. 14, 2006, now U.S. Pat. No. 7,622,583, which issued Nov. 24, 2009.The disclosures of these priority applications are incorporated hereinin their entirety.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The present invention described herein was supported at least in part byNIH (U19-AI056690). The government has certain rights in the invention.

BACKGROUND

The present invention provides compounds, pharmaceutical compositionscontaining one or more of those compounds or their pharmaceuticallyacceptable salts, which are effective in inhibiting the binding orfunction of various chemokines to chemokine receptors. As antagonists ormodulators of chemokine receptors, the compounds and compositions haveutility in treating various immune disorder conditions and diseases.

Chemokines, also known as chemotactic cytokines, are a group of smallmolecular-weight proteins that are released by a wide variety of cellsand have a variety of biological activities. Chemokines attract varioustypes of cells of the immune system, such as macrophages, T cells,eosinophils, basophils and neutrophils, and cause them to migrate fromthe blood to various lymphoid and none-lymphoid tissues. They mediateinfiltration of inflammatory cells to sites of inflammation, and areresponsible for the initiation and perpetuation of many inflammationdiseases (reviewed in Schall, Cytokine, 3:165-183 (1991), Schall et al.,Curr. Opin. Immunol., 6:865-873 (1994)).

In addition to stimulating chemotaxis, chemokines can induce otherchanges in responsive cells, including changes in cell shape, granuleexocytosis, integrin upregulation, formation of bioactive lipids (e.g.,leukotrienes), respiratory burst associated with leukocyte activation,cell proliferation, resistance to induction of apoptosis andangiogenesis. Thus, chemokines are early triggers of the inflammatoryresponse, causing inflammatory mediator release, chemotaxis andextravasation to sites of infection or inflammation. They are alsostimulators of a multitude of cellular processes that bear importantphysiological functions as well as pathological consequences.

Chemokines exert their effects by activating chemokine receptorsexpressed by responsive cells. Chemokine receptors are a class ofG-protein coupled receptors, also known as seven-transmembranereceptors, found on the surface of a wide variety of cell types such asleukocytes, endothelial cells, smooth muscle cells and tumor cells.

Chemokines and chemokine receptors are expressed by intrinsic renalcells and infiltrating cells during renal inflammation (Segerer et al.,J. Am. Soc. Nephrol., 11:152-76 (2000); Morii et al., J. DiabetesComplications, 17:11-5 (2003); Lloyd et al. J. Exp. Med., 185:1371-80(1997); Gonzalez-Cuadrado et al. Clin. Exp. Immunol, 106:518-22 (1996);Eddy & Giachelli, Kidney Int., 47:1546-57 (1995); Diamond et al., Am. J.Physiol., 266:F926-33 (1994)). In humans, CCR2 and ligand MCP-1 areamong the proteins expressed in renal fibrosis, and are correlated withthe extent of macrophage infiltration into the interstitium (Yang etal., Zhonghua Yi Xue Za Zhi, 81:73-7 (2001); Stephan et al., J. Urol.,167:1497-502 (2002); Amann et al., Diabetes Care, 26:2421-5 (2003); Daiet al., Chin. Med. J. (Engl), 114:864-8 (2001)). In animal models ofrenal fibrosis, blockade of CCR2 or MCP-1 leads to a marked reduction inseverity of renal inflammation (Kitagawa et al., Am. J. Pathol.,165:237-46 (2004); Wada et al., Am. J. Pathol., 165:237-46 (2004);Shimizu et al., J. Am. Soc. Nephrol., 14:1496-505 (2003)).

Rheumatoid arthritis is a chronic disease of the joints characterized bysynovial inflammation that leads to the destruction of cartilage andbone. Although the underlying causes of the disease are unknown, it isbelieved that macrophages and Th-1 type T cells play a key role in theinitiation and perpetuation of the chronic inflammatory process(Vervoordeldonk et al., Curr. Rheumatol. Rep., 4:208-17 (2002)).

MCP-1 is among the several chemokines, including MIP-1α and IL-8,identified in rheumatoid synovium (Villiger et al., J. Immunol.,149:722-7 (1992); Scaife et al., Rheumatology (Oxford), 43:1346-52(2004); Shadidi et al., Scand. J. Immunol., 57:192-8 (2003); Taylor etal., Arthritis Rheum., 43:38-47 (2000); Tucci et al., Biomed. Sci.Instrum., 34:169-74 (1997)). Chemokine receptors CCR1, CCR2, CCR3 andCCR5 are up-regulated in the joints from arthritic mice (Plater-Zyberket al., Immunol. Lett., 57:117-20 (1997). Blockade of MCP-1 activityusing a CCR2 antagonist or an antibody against MCP-1 have been shownefficacious in reducing joint inflammation in experimental models ofrheumatoid arthritis (Gong et al., J. Exp. Med., 186:131-7 (1997); Ogataet al., J. Pathol., 182:106-14 (1997)).

Chemokine receptor-mediated infiltration of macrophages in the fattissues may also contribute to the complications arising from obesity, acondition resulting from excessive storage of fat in the body. Obesitypredisposes the affected individuals to many disorders, such asnon-insulin-dependent diabetes, hypertension, stroke, and coronaryartery disease. In obesity, adipose tissues have altered metabolic andendocrine functions that lead to an increased release of fatty acids,hormones, and pro-inflammatory molecules. Adipose tissue macrophages arebelieved to be a key source of pro-inflammatory cytokines includingTNF-alpha, iNOS and IL-6 (Weisberg et al., J. Clin. Invest.,112:1796-808 (2003)). Recruitment of macrophages to the adipose tissueis likely mediated by MCP-1 produced by adipocytes (Christiansen T, etal., Int J Obes (Lond). 2005 January; 29(1):146-50; Sartipy et al.,Proc. Natl. Acad. Sci. U.S.A., 100:7265-70 (2003)).

Elevated MCP-1 may induce adipocyte differentiation and insulinresistance, and contribute to pathologies associated withhyper-insulinemia and obesity. MCP-1 is over-expressed in plasma inobese mice compared to lean controls and white adipose is a majorsource. MCP-1 has also been shown to accelerate wound healing, and has adirect angiogenic effect on epithelial cells, and may play a direct rolein the remodeling of adipose tissue in obesity. (Sartipy P, Loskutoff DJ., Proc. Natl. Acad. Sci. U.S.A., 100:7265 (2003)).

MCP-1 plasma levels are substantially increased in Diet Induce Obesity(DIO) mice, and a strong correlation between plasma MCP-1 levels andbody weight has been identified. Furthermore, elevation of MCP-1 inducedby high fat diet causes changes in the CD11b positive monocytepopulation in DIO mice. (Takahashi K, et al., J. Biol. Chem., 46654(2003)).

Furthermore, chronic inflammation in fat is thought to play a crucialrole in the development of obesity-related insulin resistance (Xu H, etal., J Clin Invest. 2003 December; 112(12): 1821-30). It has beenproposed that obesity related insulin resistance is, at least in part, achronic inflammatory disease initiated in adipose tissue. Manyinflammation and macrophage specific genes are dramatically upregulatedin white adipose tissue in mouse models of genetic and high fatdiet-induced obesity (DIO), and this upregulation precedes a dramaticincrease in circulating insulin.

Increased expression levels of monocyte CCR2 and monocytechemoattractant protein-1 in patients with diabetes mellitus(Biochemical and Biophysical Research Communications, 344(3):780-5(2006)) were found in a study involving diabetic patients. Serum MCP-1concentrations and surface expression of CCR2 on monocytes in diabeticpatients were significantly higher than in non-diabetics, and the serumMCP-1 levels correlated with HbA1c, triglycerides, BMI, hs-CRP. Surfaceexpression levels of CD36 and CD68 on monocytes were significantlyincreased in diabetic patients and more unregulated by MCP-1 indiabetics, augmenting uptake of ox-LDL, and hence potentially foam celltransformation. Elevated serum MCP-1 and increased monocyte CCR2, CD36,CD68 expression correlated with poor blood glucose control andpotentially correlate with increased vessel wall monocyte recruitment.

MCP-1 is a potential player in negative cross talk between adiposetissue and skeletal muscle (Bianco J J, et al., Endocrinology, 2458(2006)). MCP-1 can significantly reduce insulin-stimulated glucoseuptake, and is a prominent inducer of insulin resistance in humanskeletal muscle cell. Adipose tissue is a major secretory and endocrineactive organ producing bioactive proteins regulating energy metabolismand insulin sensitivity.

CCR2 modulates inflammatory and metabolic effects of high-fat feeding(Weisberg S P, et al., J. Clin. Invest., 115 (2006)). Genetic deficiencyin CCR2 reduced food intake and attenuated the development of obesity inmice fed a high fat diet. In obese mice matched for adiposity, CCR2deficiency reduced macrophage content and inflammatory profile ofadipose tissue, increased adiponectin expression, and improved glucosehomeostatis and insulin sensitivity. In lean animals, no effect of CCR2genotype on metabolic trait was found. In high-fat diet mice, CCR2genotype modulated feeding, the development of obesity and adiposetissue inflammation. Once established, short term antagonism was shownto attenuate macrophage accumulation in adipose tissue and insulinresistance.

Chemokine and chemokine receptors are the key regulators of immune celltrafficking. MCP-1 is a potent chemoattractant of monocytes and T cells;its expression is induced under inflammatory conditions includingproinflammatory cytokine stimulations and hypoxia. The interactionbetween MCP-1 and CCR2 mediates migration of monocytes, macrophage aswell as activated T cells and play a key role in the pathogenesis ofmany inflammatory diseases. Inhibition of CCR2 functions using smallmolecule antagonists described in this invention represents a newapproach for the treatments of inflammatory disorders.

Psoriasis is a chronic inflammatory disease characterized byhyperproliferation of keratinocytes and pronounced leukocyteinfiltration. It is known that keratinocytes from psoriasis lesionexpress abundant CCR2 ligand MCP-1, particularly when stimulated byproinflammatory cytokines such as TNF-α (Vestergaard et al., Acta. Derm.Venereol., 84(5):353-8 (2004); Gillitzer et al., J. Invest. Dermatol.,101(2):127-31 (1993); Deleuran et al., J. Dermatol. Sci., 13(3):228-36(1996)). Since MCP-1 can attract migration of both macrophages anddendritic cells expressing CCR2 to the skin, this receptor and ligandpair is believed to be important in regulating the interaction betweenproliferating keratinocytes and dermal macrophage during the developmentof psoriasis. A small molecule antagonist may thus be useful in thetreatment of psoriasis.

In addition to inflammatory diseases, chemokines and chemokine receptorshave also been implicated in cancers (Broek et al., Br. J. Cancer,88(6):855-62 (2003)). Tumor cells stimulate the formation of stroma thatsecretes various mediators pivotal for tumor growth, including growthfactors, cytokines, and proteases. It is known that the level of MCP-1is associated significantly with tumor-associated macrophageaccumulation, and prognostic analysis reveals that high expression ofMCP-1 is a significant indicator of early relapse in breast cancer (Uenoet al., Clin. Cancer Res., 6(8):3282-9 (2001)). A small moleculeantagonist of a chemokine may thus be able to reduce the release ofgrowth-stimulating cytokines by blocking accumulation of macrophages atsites of tumor formation.

T lymphocyte (T cell) infiltration into the small intestine and colonhas been linked to the pathogenesis of Coeliac diseases, food allergies,rheumatoid arthritis, human inflammatory bowel diseases (IBD) whichinclude Crohn's disease and ulcerative colitis. Blocking trafficking ofrelevant T cell populations to the intestine can lead to an effectiveapproach to treat human IBD. More recently, chemokine receptor 9 (CCR9)has been noted to be expressed on gut-homing T cells in peripheralblood, elevated in patients with small bowel inflammation such asCrohn's disease and celiac disease. The only CCR9 ligand identified todate, TECK (thymus-expressed chemokine) is expressed in the smallintestine and the ligand receptor pair is now thought to play a pivotalrole in the development of IBD. In particular, this pair mediates themigration of disease causing T cells to the intestine. See for example,Zaballos et al., J. Immunol., 162(10):5671 5675 (1999); Kunkel et al.,J. Exp. Med., 192(5):761-768 (2000); Papadakis et al., J. Immunol.,165(9):5069-5076 (2000); Papadakis et al., Gastroenterology,121(2):246-254 (2001); Campbell et al., J. Exp. Med., 195(1):135-141(2002); Wurbel et al., Blood, 98(9):2626-2632 (2001); and Uehara et al.,J. Immunol., 168(6):2811-2819 (2002). Rivera-Nieves, et al.,Gastroenterology, 2006 November; 131(5):1518-29; and Kontoyiannis etal., J. Exp. Med., Vol. 196, Number 12, Dec. 16, 2002. In addition CCR9bearing lymphocytes have been show to mediate the pathology offilariasis (lymphatic filarial disease) and inhibition of CCR9 has beencorrelated with reduction of the pathology associated with suchconditions. See for example Babu et al., Journal of Infectious Diseases,191: 1018-26, 2005.

PCT Published Application WO 2003/099773 (Millennium Pharmaceuticals,Inc.) discloses compounds which can bind to CCR9 receptors of theformula

PCT Published Application WO 2005/004810 (Merck & Co., Inc.) disclosesbrandykinin B1 antagonists or inverse agonists of the formula

US Published Patent Application 2007/0037794 A1 (ChemoCentryx, Inc.)discloses CCR2 modulators of the formula

BRIEF SUMMARY

The present invention is directed to compounds and pharmaceuticallyacceptable salts thereof, compositions, and methods useful in modulatingchemokine activity. The compounds and salts thereof, compositions, andmethods described herein are useful in treating or preventingchemokine-mediated conditions or diseases, including certaininflammatory and immunoregulatory disorders and diseases.

The compounds of the present invention have been shown to modulate oneor more of CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR3,CXCR4, CXCR5, and CX3CR1. In particular, various compounds of thepresent invention modulate CCR2 and CCR9 as shown in the examples.

In one embodiment, the present compound may be represented by formula(I) or salts thereof:

where Ar, R₁, Y₁, Y₂, Y₃, Y₄, L, and Z₁ are as defined below.

In another aspect, the present invention provides compositions useful inmodulating chemokine activity. In one embodiment, a compositionaccording to the present invention comprises a compound according to theinvention and a pharmaceutically acceptable carrier or excipient.

In yet another aspect, the present invention provides a method ofmodulating chemokine function in a cell, comprising contacting the cellwith a therapeutically effective amount of a compound or compositionaccording to the invention.

In still another aspect, the present invention provides a method formodulating chemokine function, comprising contacting a chemokinereceptor with a therapeutically effective amount of a compound orcomposition according to the invention.

In still another aspect, the present invention provides a method fortreating a chemokine-mediated condition or disease, comprisingadministering to a subject a safe and effective amount of a compound orcomposition according to the invention.

In addition to the compounds provided herein, the present inventionfurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods for the use of these compounds intherapeutic methods, primarily to treat diseases associated withchemokine signaling activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a plot of joint diameter measurements taken of Female Lewisrats (approximately 0.2 kilograms) using a compound of the invention aswell as controls.

DETAILED DESCRIPTION

General

The present invention is directed to compounds and salts thereof,compositions and methods useful in the modulation of chemokine receptorfunction, particularly CCR2 or CCR9 function. Modulation of chemokinereceptor activity, as used herein in its various forms, is intended toencompass antagonism, agonism, partial antagonism, inverse agonismand/or partial agonism of the activity associated with a particularchemokine receptor, preferably the CCR2 or CCR9 receptor. Accordingly,the compounds of the present invention are compounds which modulate atleast one function or characteristic of mammalian CCR2 or CCR9, forexample, a human CCR2 or CCR9 protein. The ability of a compound tomodulate the function of CCR2 or CCR9, can be demonstrated in a bindingassay (e.g., ligand binding or agonist binding), a migration assay, asignaling assay (e.g., activation of a mammalian G protein, induction ofrapid and transient increase in the concentration of cytosolic freecalcium), and/or cellular response assay (e.g., stimulation ofchemotaxis, exocytosis or inflammatory mediator release by leukocytes).

Abbreviations and Definitions

When describing the compounds, compositions, methods and processes ofthis invention, the following terms have the following meanings, unlessotherwise indicated.

“Alkyl” by itself or as part of another substituent refers to ahydrocarbon group which may be linear, cyclic, or branched or acombination thereof having the number of carbon atoms designated (i.e.,C₁₋₈ means one to eight carbon atoms). Examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl,cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.Alkyl groups can be substituted or unsubstituted, unless otherwiseindicated. Examples of substituted alkyl include haloalkyl, thioalkyl,aminoalkyl, and the like.

“Alkoxy” refers to —O-alkyl. Examples of an alkoxy group includemethoxy, ethoxy, n-propoxy etc.

“Alkenyl” refers to an unsaturated hydrocarbon group which may belinear, cyclic or branched or a combination thereof. Alkenyl groups with2-8 carbon atoms are preferred. The alkenyl group may contain 1, 2 or 3carbon-carbon double bonds. Examples of alkenyl groups include ethenyl,n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, cyclohexenyl,cyclopentenyl and the like. Alkenyl groups can be substituted orunsubstituted, unless otherwise indicated.

“Alkynyl” refers to an unsaturated hydrocarbon group which may belinear, cyclic or branched or a combination thereof. Alkynyl groups with2-8 carbon atoms are preferred. The alkynyl group may contain 1, 2 or 3carbon-carbon triple bonds. Examples of alkynyl groups include ethynyl,n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like. Alkynyl groups canbe substituted or unsubstituted, unless otherwise indicated.

“Aryl” refers to a polyunsaturated, aromatic hydrocarbon group having asingle ring (monocyclic) or multiple rings (bicyclic), which can befused together or linked covalently. Aryl groups with 6-10 carbon atomsare preferred, where this number of carbon atoms can be designated byC₆₋₁₀, for example. Examples of aryl groups include phenyl andnaphthalene-1-yl, naphthalene-2-yl, biphenyl and the like. Aryl groupscan be substituted or unsubstituted, unless otherwise indicated.

“Halo” or “halogen”, by itself or as part of a substituent refers to achlorine, bromine, iodine, or fluorine atom.

“Haloalkyl”, as a substituted alkyl group, refers to a monohaloalkyl orpolyhaloalkyl group, most typically substituted with from 1-3 halogenatoms. Examples include 1-chloroethyl, 3-bromopropyl, trifluoromethyland the like.

“Heterocyclyl” refers to a saturated or unsaturated non-aromatic ringcontaining at least one heteroatom (typically 1 to 5 heteroatoms)selected from nitrogen, oxygen or sulfur. The heterocyclyl ring may bemonocyclic or bicyclic. Preferably, these groups contain 0-5 nitrogenatoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably, thesegroups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygenatoms. Examples of heterocycle groups include pyrrolidine, piperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine,1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide,thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline,thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidineand the like. Preferred heterocyclic groups are monocyclic, though theymay be fused or linked covalently to an aryl or heteroaryl ring system.

In one preferred embodiment, heterocyclic groups may be represented byformula (AA) below:

where formula (AA) is attached via a free valence on either M¹ or M²; M¹represents O, NR^(e), or S(O)_(l); M² represents CR^(f)R^(g), O,S(O)_(l), or NR^(e); l is 0, 1 or 2; j is 1, 2 or 3 and k is 1, 2 or 3,with the proviso that j+k is 3, 4, or 5; and R^(a), R^(b), R^(c), R^(d),R^(e), R^(f), and R^(g) are independently selected from the groupconsisting of hydrogen, halogen, unsubstituted or substituted C₁₋₈alkyl, unsubstituted or substituted C₂₋₈ alkenyl, unsubstituted orsubstituted C₂₋₈ alkynyl, —COR^(h), —CO₂R^(h), —CONR^(h)R^(i),—NR^(h)COR^(i), —SO₂R^(h), —SO₂NR^(h)R^(i), —NSO₂R^(h)R^(i)—NR^(h)R^(i),—OR^(h), -Q¹COR^(h), -Q¹CO₂R^(h), -Q¹CONR^(h)R^(i), -Q¹NR^(h)COR^(i),-Q¹SO₂R²⁸, -Q¹SO₂N R^(h)R^(i), -Q¹NSO₂R^(h)R^(i), -Q¹NR^(h)R^(i),-Q¹OR^(h), wherein Q¹ is a member selected from the group consisting ofC₁₋₄ alkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene, and R^(h) and R^(i)are independently selected from the group consisting of hydrogen andC₁₋₈ alkyl, and wherein the aliphatic portions of each of the R^(a),R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h) and R^(i) substituentsare optionally substituted with from one to three members selected fromthe group consisting of halogen, —OH, —OR^(n), —OC(O)NHR^(n),—OC(O)NR^(n)R^(o), —SH, —SR^(n), —S(O)R^(n), —S(O)₂R^(n), —SO₂NH₂,—S(O)₂NHR^(n), —S(O)₂NR^(n)R^(o), —NHS(O)₂R^(n), —NR^(n)S(O)₂R^(o),—C(O)NH₂, —C(O)NHR^(n), —C(O)NR^(n)R^(o), —C(O)R^(n), —NHC(O)R^(o),—NR^(n)C(O)R^(o), —NHC(O)NH₂, —NR^(n)C(O)NH₂, —NR^(n)C(O)NHR^(o),—NHC(O)NHR^(n), —NR^(n)C(O)NR^(o)R^(p), —NHC(O)NR^(n)R^(o), —CO₂H,—CO₂R^(n), —NH CO₂R^(n), —NR^(n)CO₂R^(o), —CN, —NO₂, —NH₂, —NHR^(n),—NR^(n)R^(o), —NR^(n)S(O)NH₂ and —NR^(n)S(O)₂NHR^(o), wherein R^(n),R^(o) and R^(p) are independently an unsubstituted C₁₋₈ alkyl.Additionally, any two of R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) andR^(g) may be combined to form a bridged or spirocyclic ring system.

In one preferred embodiment, the number of R^(a)+R^(b)+R^(c)+R^(d)groups that are other than hydrogen is 0, 1 or 2. In a more preferredembodiment, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), and R^(g) areindependently selected from the group consisting of hydrogen, halogen,unsubstituted or substituted C₁₋₈ alkyl, —COR^(h), —CO₂R^(h),—CONR^(h)R^(h), —NR^(h)COR^(h), —SO₂R^(h), —SO₂NR^(h)R^(i),—NSO₂R^(h)R^(i), —NR^(h)R^(i), and —OR^(h), wherein R^(h) and R^(i) areindependently selected from the group consisting of hydrogen andunsubstituted C₁₋₈ alkyl and wherein the aliphatic portions of each ofthe R^(a), R^(b), R^(c), R^(d), R^(e), R^(f) and R^(g) substituents areoptionally substituted with from one to three members selected from thegroup consisting of halogen, —OH, —OR^(n), —OC(O)NHR^(n),—OC(O)NR^(n)R^(o), —SH, —SR^(n), —S(O)R^(o), —S(O)₂R^(n), —SO₂NH₂,—S(O)₂NHR^(n), —S(O)₂NR^(n)R^(o), —NHS(O)₂R^(n), —NR^(n)S(O)₂R^(o),—C(O)NH₂, —C(O)NHR^(n), —C(O)NR^(n)R^(o), —C(O)R^(n), —NHC(O)R^(n),—NR^(n)C(O)R^(o), —NHC(O)NH₂, —NR^(n)C(O)NH₂, —NR^(n)C(O)NHR^(o),—NHC(O)NHR^(n), —NR^(n)C(O)NR^(o)R^(p), —NHC(O)NR^(n)R^(o), —CO₂H,—CO₂R^(n), —NH CO₂R^(n), —NR^(n)CO₂R^(o), —CN, —NO₂, —NH₂, —NHR^(n),—NR^(n)R^(o), —NR^(n)S(O)NH₂ and —NR^(n)S(O)₂NHR^(o), wherein R^(n),R^(o) and R^(p) are independently an unsubstituted C₁₋₈ alkyl.

In a more preferred embodiment, R^(a), R^(b), R^(c), R^(d), R^(e),R^(f), and R^(g) are independently hydrogen or C₁₋₄ alkyl. In anotherpreferred embodiment, at least three of R^(a), R^(b), R^(c), R^(d),R^(e), R^(f), and R^(g) are hydrogen.

“Heteroaryl” refers to an aromatic group containing at least oneheteroatom, where the heteroaryl group may be monocyclic or bicyclic.Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl,triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl,benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl,azaindolyl, azaindazolyl, quinolyl, isoquinolyl, isothiazolyl,pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl,furyl or thienyl. Preferred heteroaryl groups are those having at leastone aryl ring nitrogen atom, such as quinolinyl, quinoxalinyl, purinyl,benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, indolyl,quinolyl, isoquinolyl and the like. Preferred 6-ring heteroaryl systemsinclude pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl and thelike. Preferred 5-ring heteroaryl systems include isothiazolyl,pyrazolyl, imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl and the like.

Heterocyclyl and heteroaryl can be attached at any available ring carbonor heteroatom. Each heterocyclyl and heteroaryl may have one or morerings. When multiple rings are present, they can be fused together orlinked covalently. Each heterocyclyl and heteroaryl must contain atleast one heteroatom (typically 1 to 5 heteroatoms) selected fromnitrogen, oxygen or sulfur. Preferably, these groups contain 0-5nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms. More preferably,these groups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygenatoms. Heterocyclyl and heteroaryl groups can be substituted orunsubstituted, unless otherwise indicated. For substituted groups, thesubstitution may be on a carbon or heteroatom. For example, when thesubstitution is oxo (═O or —O⁻), the resulting group may have either acarbonyl (—C(O)—) or a N-oxide (—N⁺—O⁻).

Suitable substituents for substituted alkyl, substituted alkenyl, andsubstituted alkynyl include halogen, —CN, —CO₂R′, —C(O)R′, —C(O)NR′R″,oxo (═O or —O—), —OR′, —OC(O)R′, —OC(O)NR′R″—NO₂, —NR′C(O)R″,—NR′″C(O)NR′R″, —NR′R″, —NR′CO₂R″, —NR'S(O)R″, —NR'S(O)₂R′″,—NR′″S(O)NR′R″, —NR′″S(O)₂NR′R″, —SR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N₃, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10-membered heterocyclyl. The numberof possible substituents range from zero to (2m′+1), where m′ is thetotal number of carbon atoms in such radical.

Suitable substituents for substituted aryl, substituted heteroaryl andsubstituted heterocyclyl include halogen, —CN, —CO₂R′, —C(O)R′,—C(O)NR′R″, oxo (═O or —O⁻), —OR′, —OC(O)R′, —OC(O)NR′R″, —NO₂,—NR′C(O)R″, —NR′″C(O)NR′R″, —NR′R″, —NR′CO₂R″, —NR′S(O)R″, —NR′S(O)₂R″,—NR′″S(O)NR′R″, —NR′″S(O)₂NR′R″, —SR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR′—C(NHR″)═NR′″, —SiR′R″R′″, —N₃, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10 membered heterocyclyl. The numberof possible substituents range from zero to the total number of openvalences on the aromatic ring system.

As used above, R′, R″ and R′″ each independently refer to a variety ofgroups including hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedaryloxyalkyl. When R′ and R″ are attached to the same nitrogen atom,they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring (for example, —NR′R″ includes 1-pyrrolidinyl and4-morpholinyl). Furthermore, R′ and R″, R″ and R′″, or R′ and R′″ maytogether with the atom(s) to which they are attached, form a substitutedor unsubstituted 5-, 6- or 7-membered ring.

Two of the substituents on adjacent atoms of an aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NR″″—, —O—,—CH₂— or a single bond, and q is an integer of from 0 to 2.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A′-(CH₂)_(r)—B′—, wherein A′ and B′ are independently —CH₂—,—O—, —NR″″—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR″″— or a single bond, and ris an integer of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR″″—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.R″″ in is selected from hydrogen or unsubstituted C₁₋₈ alkyl.

“Heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S)and silicon (Si).

“Pharmaceutically acceptable” carrier, diluent, or excipient is acarrier, diluent, or excipient compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

“Pharmaceutically-acceptable salt” refers to a salt which is acceptablefor administration to a patient, such as a mammal (e.g., salts havingacceptable mammalian safety for a given dosage regime). Such salts canbe derived from pharmaceutically-acceptable inorganic or organic basesand from pharmaceutically-acceptable inorganic or organic acids,depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Salts derived from pharmaceutically-acceptable inorganic bases includealuminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, manganous, potassium, sodium, zinc and the like.Salts derived from pharmaceutically-acceptable organic bases includesalts of primary, secondary, tertiary and quaternary amines, includingsubstituted amines, cyclic amines, naturally-occurring amines and thelike, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Salts derivedfrom pharmaceutically-acceptable acids include acetic, ascorbic,benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic,fumaric, gluconic, glucoronic, glutamic, hippuric, hydrobromic,hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic,methanesulfonic, mucic, naphthalenesulfonic, nicotinic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicand the like.

Also included are salts of amino acids such as arginate and the like,and salts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge, S. M. et al, “Pharmaceutical Salts”, J.Pharmaceutical Science, 1977, 66:1-19). Certain specific compounds ofthe present invention contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

“Salt thereof” refers to a compound formed when the hydrogen of an acidis replaced by a cation, such as a metal cation or an organic cation andthe like. Preferably, the salt is a pharmaceutically-acceptable salt,although this is not required for salts of intermediate compounds whichare not intended for administration to a patient.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

“Therapeutically effective amount” refers to an amount sufficient toeffect treatment when administered to a patient in need of treatment.

“Treating” or “treatment” as used herein refers to the treating ortreatment of a disease or medical condition (such as a viral, bacterialor fungal infection or other infectious diseases, as well as autoimmuneor inflammatory conditions) in a patient, such as a mammal (particularlya human or a companion animal) which includes ameliorating the diseaseor medical condition, i.e., eliminating or causing regression of thedisease or medical condition in a patient; suppressing the disease ormedical condition, i.e., slowing or arresting the development of thedisease or medical condition in a patient; or alleviating the symptomsof the disease or medical condition in a patient.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, bothsolvated forms and unsolvated forms are intended to be encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms(i.e., as polymorphs). In general, all physical forms are equivalent forthe uses contemplated by the present invention and are intended to bewithin the scope of the present invention.

It will be apparent to one skilled in the art that certain compounds ofthe present invention may exist in tautomeric forms, all such tautomericforms of the compounds being within the scope of the invention. Certaincompounds of the present invention possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers (e.g., separate enantiomers)are all intended to be encompassed within the scope of the presentinvention. The compounds of the present invention may also containunnatural proportions of atomic isotopes at one or more of the atomsthat constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

Compounds that Modulate CCR2 or CCR9 Activity

The present invention provides compounds that modulate at least one ofCCR2 or CCR9 activity. Chemokine receptors are integral membraneproteins which interact with an extracellular ligand, such as achemokine, and mediate a cellular response to the ligand, e.g.,chemotaxis, increased intracellular calcium ion concentration, etc.Therefore, modulation of a chemokine receptor function, e.g.,interference with a chemokine receptor ligand interaction, will modulatea chemokine receptor mediated response, and treat or prevent a chemokinereceptor mediated condition or disease. Modulation of a chemokinereceptor function includes both inducement and inhibition of thefunction. The type of modulation accomplished will depend on thecharacteristics of the compound, i.e., antagonist or full, partial orinverse agonist.

Without intending to be bound by any particular theory, it is believedthat the compounds provided herein interfere with the interactionbetween a chemokine receptor and one or more cognate ligands. Inparticular, it is believed that the compounds interfere with theinteraction between CCR2 and a CCR2 ligand, such as MCP-1. Compoundscontemplated by the invention include, but are not limited to, theexemplary compounds provided herein and salts thereof.

For example, compounds of this invention act as potent CCR2 antagonists,and this antagonistic activity has been further confirmed in animaltesting for inflammation, one of the hallmark disease states for CCR2.Accordingly, the compounds provided herein are useful in pharmaceuticalcompositions, methods for the treatment of CCR2-mediated diseases, andas controls in assays for the identification of competitive CCR2antagonists.

The compounds of the invention are thought to interfere withinappropriate T-cell trafficking by specifically modulating orinhibiting a chemokine receptor function. Without intending to be boundby any particular theory, it is believed that the compounds providedherein interfere with the interaction between a chemokine receptor andone or more cognate ligands. In particular, it is believed that thecompounds interfere with the interaction between CCR9 and a CCR9 ligand,such as TECK. Compounds contemplated by the invention include, but arenot limited to, the exemplary compounds provided herein and saltsthereof.

For example, compounds of this invention act as potent CCR9 antagonists,and this antagonistic activity has been further confirmed in animaltesting for inflammation, one of the hallmark disease states for CCR9.Accordingly, the compounds provided herein are useful in pharmaceuticalcompositions, methods for the treatment of CCR9-mediated diseases, andas controls in assays for the identification of competitive CCR9antagonists.

Compounds

In one embodiment, the compounds of the present invention arerepresented by formula (I), or salts thereof:

Ar is selected from the group consisting of substituted or unsubstitutedC₆₋₁₀ aryl and substituted or unsubstituted 5- to 10-memberedheteroaryl.

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, and substituted orunsubstituted 3- to 10-membered heterocyclyl;

Y¹ is selected from the group consisting of —CR^(2a)—, —N—, and—N⁺(O)⁻—;

Y² is selected from the group consisting of —CR^(2b)—, —N—, and—N⁺(O)⁻—;

Y³ is selected from the group consisting of —CR^(2b)—, —N—, and—N⁺(O)⁻—;

Y⁴ is selected from the group consisting of —CR^(2d)—, —N—, and—N⁺(O)⁻—;

R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected fromthe group consisting of hydrogen, halogen, —CN, —C(O)R³, —CO₂R³,—C(O)NR³R⁴, —OR³, —OC(O)R³, —OC(O)NR³R⁴, —SR³, —S(O)R³, —S(O)₂R³,—S(O)₂NR³R⁴, —NO₂, —NR³R⁴, —NR³C(O)R⁴, —NR³C(O)OR⁴, —NR³S(O)₂R⁴,—NR³C(O)NR⁴R⁵, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₆₋₁₀ aryl, and substituted or unsubstituted 5- to10-membered heteroaryl;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl;

R³ and R⁴, R⁴ and R⁵ or R³ and R⁵ may, together with the atoms to whichthey are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring;

L is selected from the group consisting of a bond, —O—, —S—, —S(O)—,—S(O)₂—, —CR⁶R⁷—, —NR⁸—, —C(O)—, —C(═N—O—R⁹)—, —C(O)NR⁸—, and —NR⁸C(O)—;

R⁶ and R⁷ are each independently selected from the group consisting ofhydrogen, halogen, substituted or unsubstituted C₁₋₈ alkyl, substitutedor unsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,—CN, —OR⁹, —NR¹¹R¹¹, —S(O)R⁹, and —S(O)₂R⁹;

R⁶ and R⁷ may, together with the carbon atom to which they are attached,form substituted or unsubstituted C₃₋₈ cycloalkyl or substituted orunsubstituted 3- to 10-membered heterocyclic ring;

R⁹ is selected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstitutedC₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryl,and substituted or unsubstituted 3- to 10-membered heterocyclyl;

R¹⁰ and R¹¹ are each independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstituted 3-to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, substitutedor unsubstituted C₂₋₈ alkenyl, and substituted or unsubstituted C₂₋₈alkynyl;

R¹⁰ and R¹¹ of —NR¹⁰R¹¹ may, together with the nitrogen, formsubstituted or unsubstituted 3- to 10-membered heterocyclyl;

R⁸ is selected from the group consisting of hydrogen, C(O)R¹², S(O)₂R¹²,CO₂R¹², substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₂₋₆ alkenyl, and substituted or unsubstituted C₂₋₆alkynyl;

R¹² is selected from the group consisting of substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,and substituted or unsubstituted 5- to 10-membered heteroaryl;

Z¹ is selected from the group consisting of substituted or unsubstitutedC₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryl,substituted or unsubstituted 3- to 10-membered heterocyclyl, and—NR¹³R¹⁴;

R¹³ and R¹⁴ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to10-membered heteroaryl, substituted or unsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀aryl), and substituted or unsubstituted (C₁₋₄ alkyl)-(5- to 10-memberedheteroaryl);

R¹³ and R¹⁴ may, together with the nitrogen, form a substituted orunsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl.

In one embodiment, the compounds of the present invention arerepresented by formula (I), or salts thereof:

where Ar is substituted or unsubstituted C₆₋₁₀ aryl;

R¹ is selected from the group consisting of hydrogen or substituted orunsubstituted C₁₋₈ alkyl;

Y¹ is —CR^(2a)—;

Y² is —CR^(2b)—;

Y³ is —CR^(2c)—;

Y⁴ is selected from the group consisting of —CR^(2d)—, —N— and —N⁺(O)⁻—;

R^(2a), R^(2b), R^(2c) and R^(2d) are each independently selected fromthe group consisting of hydrogen, halogen, substituted or unsubstitutedC₁₋₈ alkyl;

L is —C(O)—, —C(═N—O—R⁹)—, or bond; and

Z¹ is substituted or unsubstituted 3- to 10-membered heterocyclic orsubstituted or unsubstituted 5- to 10-membered heteroaryl.

In one embodiment of formula (I), the compound is of the formula (Ia) ora salt thereof:

where X³ and X⁴ are each independently hydrogen, halogen, substituted orunsubstituted C₁₋₈ alkyl, —CN, or C₁₋₈ haloalkyl, provided that at leastone of X³ or X⁴ is other than hydrogen;

each X², X⁵, and X⁶ is independently hydrogen, halogen, or substitutedor unsubstituted C₁₋₄ alkyl;

R¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

Y⁶ is halogen or substituted or unsubstituted C₁₋₈ alkyl;

Y⁷ is hydrogen or substituted or unsubstituted C₁₋₄ alkyl;

L is selected from the group consisting of a bond, —C(O)—, and—C(═N—O—R⁹)—;

Z⁶ and Z⁷ are each independently selected from the group consisting of—CR⁶⁷—, —N—, and —N⁺(O)⁻—;

Y⁴ is —CR^(2a)—, —N—, or —N⁺(O)⁻—;

Z³ and Z⁵ are —N—, or —N⁺(O)⁻—; and

Z⁴ is —CR⁶⁷—;

R¹⁰⁰ is selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl andsubstituted or unsubstituted 3- to 10-membered heterocycle;

each R⁶⁷ is independently selected from the group consisting ofhydrogen, halogen, substituted or unsubstituted C₁₋₈ alkyl, substitutedor unsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈alkynyl, —CN, ═O, —NO₂, —OR⁶⁸, —OC(O)R⁶⁸, —CO₂R⁶⁸, —C(O)R⁶⁸,—C(O)NR⁶⁹R⁶⁸, —OC(O)NR⁶⁹R⁶⁸, —NR⁷⁰C(O)R⁶⁸, —NR⁷⁰C(O)NR⁶⁹R⁶⁸, —NR⁶⁹R⁶⁸,—NR⁷⁰CO₂R⁶⁸, —SR⁶⁸, —S(O)R⁶⁸, —S(O)₂R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸, —NR⁷⁰S(O)₂R⁶⁸,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl and substituted or unsubstituted 3- to10-membered heterocyclyl;

each occurrence of R⁶⁸, R⁶⁹, and R⁷⁰ is independently selected from thegroup consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,aryl, or heteroaryl; or R⁶⁹ and R⁶⁸ or R⁷⁰ and R⁶⁸, together with theatom(s) to which they are attached, form an substituted or unsubstituted5-, 6-, or 7-membered ring; and

where R^(2a) is as defined for formula (I).

In another embodiment of formula (I), the compound is of the formula(Ib) or a salt thereof:

where R¹, X³, X⁴, Y⁶, and R¹⁰⁰ are as described for formula (Ia).

In another embodiment of formula (I), the compound is of the formula(Ic) or a salt thereof:

where X³ and X⁴ are each independently hydrogen, halogen, substituted orunsubstituted C₁₋₈ alkyl, —CN, or C₁₋₈ haloalkyl, provided that at leastone of X³ or X⁴ is other than hydrogen;

each X², X⁵, X⁶ is independently hydrogen, halogen, or substituted orunsubstituted C₁₋₄ alkyl;

R¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

Y⁶ is halogen or substituted or unsubstituted C₁₋₈ alkyl;

Y⁷ is hydrogen or substituted or unsubstituted C₁₋₄ alkyl;

R¹⁰⁰ is selected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-memberedheteroaryl and substituted or unsubstituted 3- to 10-memberedheterocycle;

L is selected from the group consisting of a bond, —C(O)—, and—C(═N—O—R⁹)—;

Y⁴ is —CR^(2a)—, —N—, or —N⁺(O)⁻—;

Z⁴ is —N—, or —N⁺(O)⁻—; and

Z³, Z⁵, Z⁶, and Z⁷ are each independently —CR⁶⁷—;

where R^(2a) and R⁶⁷ are as defined for formula (I).

In another embodiment of formula (I), the compound is of the formula(Id):

where X³, X⁴, R¹, Y⁶, and R¹⁰⁰ are as described for formula (Ic).

In another embodiment of formula (I), the compound of the formula (Ie)or a salt thereof:

where X³ and X⁴ are each independently hydrogen, halogen, substituted orunsubstituted C₁₋₈ alkyl, —CN, or C₁₋₈ haloalkyl, provided that at leastone of X³ or X⁴ is other than hydrogen;

each X², X⁵, and X⁶ is independently hydrogen, halogen, or substitutedor unsubstituted C₁₋₄ alkyl;

R¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

Y⁶ is halogen or substituted or unsubstituted C₁₋₈ alkyl;

Y⁷ is hydrogen or substituted or unsubstituted C₁₋₄ alkyl;

R¹⁰⁰ is selected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstitutedC₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryland substituted or unsubstituted 3- to 10-membered heterocycle;

L is selected from the group consisting of a bond, —C(O)—, and—C(═N—O—R⁹)—;

Y⁴ is —CR^(2a)—, —N—, or —N⁺(O)⁻—;

Z³ and Z⁴ are each independently —CR⁶⁷—;

Z⁵ is —N—, or —N⁺(O)⁻—;

Z⁶ and Z⁷ are each independently —CR⁶⁷—, —N—, or —N⁺(O)⁻—; and

where R^(2a) is as defined for formula (I) and R⁶⁷ is as defined forformula (Ia).

In another embodiment of formula (I), the compound is of the formula(If):

where X³, X⁴, R¹, Y⁶, R¹⁰⁰ and Z⁵ are as described for formula (Ie).

In another embodiment of formula (I), the compound is of the formula(Ig):

where X³, X⁴, R¹, Y⁶, R¹⁰⁰ and Z⁵ are as described for formula (Ie).

In a further embodiment, the compounds of the present invention arerepresented by formula (I), or salts thereof:

Ar is selected from the group consisting of substituted or unsubstitutedC₆₋₁₀ aryl and substituted or unsubstituted 5- to 10-memberedheteroaryl.

R¹ is selected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, and substituted orunsubstituted 3- to 10-membered heterocyclyl;

Y¹ is selected from the group consisting of —CR^(2a)—, —N—, and—N⁺(O)⁻—;

Y² is selected from the group consisting of —CR^(2b)—, —N—, and—N⁺(O)⁻—;

Y³ is selected from the group consisting of —CR^(2c)—, —N—, and—N⁺(O)⁻—;

R^(2a), R^(2b), and R^(2c) are each independently selected from thegroup consisting of hydrogen, halogen, —CN, —C(O)R³, —CO₂R³, —C(O)NR³R⁴,—OR³, —OC(O)R³, —OC(O)NR³R⁴, —SR³, —S(O)R³, —S(O)₂R³, —S(O)₂NR³R⁴, —NO₂,—NR³R⁴, —NR³C(O)R⁴, —NR³C(O)OR⁴, —NR³S(O)₂R⁴, —NR³C(O)NR⁴R⁵, substitutedor unsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,and substituted or unsubstituted 5- to 10-membered heteroaryl;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl;

R³ and R⁴, R⁴ and R⁵ or R³ and R⁵ may, together with the atoms to whichthey are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring;

Y⁴ is selected from the group consisting of —N— and —N⁺(O)⁻—;

L is selected from the group consisting of a bond, —O—, —S—, —S(O)—,—S(O)₂—, —CR⁶R⁷—, —NR⁸—, —C(O)—, —C(O)NR⁸—, and —NR⁸C(O)—;

R⁶ and R⁷ are each independently selected from the group consisting ofhydrogen, halogen, substituted or unsubstituted C₁₋₈ alkyl, substitutedor unsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,—CN, —OR⁹, —NR¹⁰R¹¹, —S(O)R⁹, and —S(O)₂R⁹;

R⁶ and R⁷ may, together with the carbon atom to which they are attached,form substituted or unsubstituted C₃₋₈ cycloalkyl or substituted orunsubstituted 3- to 10-membered heterocyclic ring;

R⁹ is selected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstitutedC₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryl,and substituted or unsubstituted 3- to 10-membered heterocyclyl;

R¹⁰ and R¹¹ are each independently selected from the group consisting ofsubstituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstituted 3-to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, substitutedor unsubstituted C₂₋₈ alkenyl, and substituted or unsubstituted C₂₋₈alkynyl;

R¹⁰ and R¹¹ of —NR¹⁰R¹¹ may, together with the nitrogen, formsubstituted or unsubstituted 3- to 10-membered heterocyclyl;

R⁸ is selected from the group consisting of hydrogen, C(O)R¹², S(O)₂R¹²,CO₂R¹², substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₂₋₆ alkenyl, and substituted or unsubstituted C₂₋₆alkynyl;

R¹² is selected from the group consisting of substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,and substituted or unsubstituted 5- to 10-membered heteroaryl;

Z¹ is selected from the group consisting of substituted or unsubstitutedC₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryl,substituted or unsubstituted 3- to 10-membered heterocyclyl, and—NR¹³R¹⁴;

R¹³ and R¹⁴ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to10-membered heteroaryl, substituted or unsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀aryl), and substituted or unsubstituted (C₁₋₄ alkyl)-(5- to 10-memberedheteroaryl); and

R¹³ and R¹⁴ may, together with the nitrogen, form a substituted orunsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl.

In a further embodiment of formula (I), the compounds are represented byformula (II), or salts thereof:

Ar, R¹, L and Z¹ are as defined above.

Y⁵, Y⁶ and Y⁷ are each independently selected from the group consistingof hydrogen, halogen, —CN, —C(O)R¹⁵, —CO₂R¹⁵, —C(O)NR¹⁵R¹⁶, —OR¹⁵,—OC(O)R¹⁵, —OC(O)NR¹⁵R¹⁶, —SR¹⁵, —S(O)R¹⁵, —S(O)₂R¹⁵, —S(O)₂NR¹⁵R¹⁶,—NO₂, —NR¹⁵R¹⁶, —NR¹⁵C(O)R¹⁶, —NR¹⁵C(O)OR¹⁶, —NR¹⁵S(O)₂R¹⁶,—NR¹⁵C(O)NR¹⁶R¹⁷, substituted or unsubstituted C₁₋₈ alkyl, substitutedor unsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl,substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl;

R¹⁵, R¹⁶ and R¹⁷ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl;

R¹⁵ and R¹⁶, R¹⁶ and R¹⁷ or R¹⁵ and R¹⁷ may, together with the atoms towhich they are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring.

In another embodiment of formula (I), the compounds are represented byformula (III), or salts thereof:

L and Z¹ are as defined above.

X², X³, X⁴, X⁵, and X⁶ are each independently selected from the groupconsisting of hydrogen, halogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, —CN, —NO₂, —C(O)R¹⁸, —CO₂R¹⁸, —C(O)NR¹⁸R¹⁹,—OR¹⁸, —OC(O)R¹⁹, —OC(O)NR¹⁸R¹⁹, —NO₂, —NR¹⁸C(O)R¹⁹, —NR¹⁸C(O)NR¹⁹R²⁰,—NR¹⁸R¹⁹, —NR¹⁸CO₂R¹⁹, —NR¹⁸S(O)₂R¹⁹, —SR¹⁸, —S(O)R¹⁸, —S(O)₂R¹⁸,—S(O)₂NR¹⁸R¹⁹, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl;

R¹⁸, R¹⁹ and R²⁰ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl;

R¹⁸ and R19, R¹⁹ and R²⁰ or R¹⁸ and R²⁰ may, together with the atoms towhich they are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring;

Y⁸, Y⁹ and Y¹⁰ are each independently selected from the group consistingof hydrogen, halogen, —CN, —NO₂, —OR²¹, —CO₂R²¹, —OC(O)R²¹,—OC(O)NR²¹R²², —C(O)NR²¹R²², —C(O)R²¹, —SR²¹, —S(O)R²¹, —S(O)₂R²¹,NR²¹R²², —NR²¹C(O)R²², —NR²¹C(O)₂R²², —NR²¹S(O)₂R²², —NR²¹C(O)NR²²R²³,substituted or unsubstituted C₁₋₈ alkyl and substituted or unsubstituted3- to 10-membered heterocyclyl,

R²¹, R²² and R²³ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl;

R²¹ and R²², R²² and R²³ or R²¹ and R²³ may, together with the atoms towhich they are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring.

Known Compound

The compound of the formula (I) where Ar para-isopropoxy phenyl, R¹ ishydrogen, Y¹, Y², Y³ are each —CH—, Y⁴ is N, L is C═O, and Z¹ is phenyl,(also known asN-(2-benzoyl-pyridin-3-yl)-4-isopropoxy-benzenesulfonamide) is known,but not as a CCR2 antagonist.

3-[N-(2-Aminophenyl)methyl-N-(4-chlorobenzenesulfonyl)]amino-2-[2-(4-chlorophenyl)aminoethyl]aminopyridineis known, but not as CCR2

Preferred Compounds

In several preferred embodiments, the compounds may be represented bythe following formulae, or salts thereof:

Formulae IV to C are examples of Formula I.

In the following descriptions and embodiments, references to specificsubstituents only correspond to formula numbers in which those specificsubstituents are present or appear.

In each of the formulae (IV to C), Ar, L and Z¹ are as defined above.

A is selected from the group consisting of —CH—, —CZ¹⁶—, —N—, and—N⁺(O)⁻—;

each occurrence of Z¹⁶ is independently selected from the groupconsisting of hydrogen, halogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, —CN, oxo (═O or —O⁻), —NO₂, —OR⁴²,—OC(O)R⁴², —CO₂R⁴², —C(O)R⁴², —C(O)NR⁴²R⁴³, —OC(O)NR⁴²R⁴³, —NR⁴²C(O)R⁴³,—NR⁴²C(O)NR⁴³R⁴⁴, —NR⁴²R⁴³, —NR⁴²CO₂R⁴³, —SR⁴², —S(O)R⁴², —S(O)₂R⁴²,—S(O)₂NR⁴²R⁴³, —NR⁴²S(O)₂R⁴³, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, substitutedor unsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀ aryl), and substituted orunsubstituted (C₁₋₄ alkyl)-(5- to 10-membered heteroaryl); or where twoor more A are CZ¹⁶, then the Z¹⁶ substituents together can form acarbocyclic or heterocyclic ring;

R⁴², R⁴³ and R⁴⁴ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted 3- to 10-membered hete65rocyclyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, and substitutedor unsubstituted 5- to 10-membered heteroaryl;

X^(a) represents 0 to 5 substituents each independently selected fromthe group consisting of halogen, —CN, —C(O)R²⁴, —CO₂R²⁴, —C(O)NR²⁴R²⁵,—OR²⁴, —OC(O)R²⁴, —OC(O)NR²⁴R²⁵, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴,—S(O)₂NR²⁴R²⁵, —NO₂, —NR²⁴R²⁵, —NR²⁴C(O)R²⁵, —NR²⁴C(O)₂R²⁵,—NR²⁴S(O)₂R²⁵, —NR²⁴C(O)NR²⁵R²⁶, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted 3- to10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, andsubstituted or unsubstituted 5- to 10-membered heteroaryl;

R²⁴, R²⁵ and R²⁶ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl; and

R²⁴ and R²⁵, R²⁵ and R²⁶ or R²⁴ and R²⁶ may, together with the atoms towhich they are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring.

X^(b) and X^(c) are each independently selected from the groupconsisting of hydrogen, halogen, —CN, —C(O)R^(24a), —CO₂R^(24a),—C(O)NR^(24a)R^(25a), —OR^(24a), —OC(O)R^(24a), —OC(O)NR^(24a)R^(25a),—SR^(24a), —S(O)R^(24a), —S(O)₂R^(24a), —S(O)₂NR^(24a)R^(25a), —NO₂,—NR^(24a)R^(25a), —NR^(24a)C(O)R^(25a), —NR^(24a)C(O)₂R^(25a),—NR^(24a)S(O)₂R^(25a), —NR^(24a)C(O)NR^(25a)R^(26a), substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,and substituted or unsubstituted 5- to 10-membered heteroaryl;

R^(24a), R^(25a) and R^(26a) are each independently selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl; and

R^(24a) and R^(25a), R^(25a) and R^(26a) or R^(24a) and R^(26a) may,together with the atoms to which they are attached, form a substitutedor unsubstituted 5-, 6-, or 7-membered ring.

Y^(a) represents 0 to 3 substituents each independently selected fromthe group consisting of halogen, —CN, —C(O)R²⁷, —CO₂R²⁷, —C(O)NR²⁷R²⁸,—OR²⁷, —OC(O)R²⁷, —OC(O)NR²⁷R²⁸, —SR²⁷, —S(O)R²⁷, —S(O)₂R²⁷,—S(O)₂NR²⁷R²⁸, —NO₂, —NR²⁷R²⁸, —NR²⁷C(O)R²⁸, —NR²⁷C(O)₂R²⁸,—NR²⁷S(O)₂R²⁸, —NR²⁷C(O)NR²⁸R²⁹, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted 3- to10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, andsubstituted or unsubstituted 5- to 10-membered heteroaryl;

R²⁷, R²⁸ and R²⁹ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl; and

R²⁷ and R²⁸, R²⁸ and R²⁹ or R²⁷ and R²⁹ may, together with the atoms towhich they are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring.

Y^(b) is independently selected from the group consisting of hydrogen,halogen, —CN, —C(O)R^(27a), —CO₂R^(27a), —C(O)NR^(27a)R^(28a),—OR^(27a), —OC(O)R^(27a), —OC(O)NR^(27a)R^(28a), —SR^(27a), —S(O)R^(7a),—S(O)₂R^(27a), —S(O)₂NR^(27a)R^(28a), —NO₂, —NR^(27a)R^(28a),—NR^(27a)C(O)R^(28a), —NR^(27a)C(O)₂R^(28a), —NR^(27a)S(O)₂R^(28a),—NR^(27a)C(O)NR^(28a)R^(29a), substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted 3- to 10-memberedheterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, and substitutedor unsubstituted 5- to 10-membered heteroaryl;

R^(27a), R^(28a) and R^(29a) are each independently selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl; and

R^(27a) and R^(28a), R^(28a) and R^(29a) or R^(27a) and R^(29a) may,together with the atoms to which they are attached, form a substitutedor unsubstituted 5-, 6-, or 7-membered ring.

Z^(a) represents 0 to 5 substituents each independently selected fromthe group consisting of halogen, —CN, —C(O)R³⁰, —CO₂R³⁰, —C(O)NR³⁰R³¹,—OR³⁰, —OC(O)R³⁰, —OC(O)NR³⁰R³¹, —SR³⁰, —S(O)R³⁰, —S(O)₂R³⁰,—S(O)₂NR³⁰R³¹, —NO₂, —NR³⁰R³¹, —NR³⁰C(O)R³¹, —NR³⁰C(O)₂R³¹,—NR³⁰S(O)₂R³¹, —NR³⁰C(O)NR³¹R³², oxo (═O or —O⁻), substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, substitutedor unsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀ aryl), and substituted orunsubstituted (C₁₋₄ alkyl)-(5- to 10-membered heteroaryl); oralternatively where two of Z^(a) together with the atoms which theysubstitute, form a carbocyclic or heterocyclic ring such that Z is a bi-or tri-cyclic ring;

R³⁰, R³¹ and R³² are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl; and

R³⁰ and R³¹, R³¹ and R³² or R³⁰ and R³² may, together with the atoms towhich they are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring.

Z^(b) is selected from the group consisting of hydrogen, halogen, —CN,—C(O)R^(30a), —CO₂R^(30a), —C(O)NR^(30a)R^(31a), —OR^(30a),—OC(O)R^(30a), —OC(O)NR^(30a)R^(31a), —SR^(30a), —S(O)R^(30a),—S(O)₂R^(30a), —S(O)₂NR^(30a)R^(31a), —NO₂, —NR^(30a)R^(31a),—NR^(30a)C(O)R^(31a), —NR^(30a)C(O)₂R^(31a), —NR^(30a)S(O)₂R^(31a),—NR^(30a)C(O)NR^(31a)R^(32a), Oxo (═O or —O⁻), substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, substitutedor unsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀ aryl), and substituted orunsubstituted (C₁₋₄ alkyl)-(5- to 10-membered heteroaryl); oralternatively where two of Z^(a) and Z^(b) together with the atoms whichthey substitute, form a carbocyclic or heterocyclic ring such that Z isa bi- or tri-cyclic ring;

R^(30a), R^(31a) and R^(32a) are each independently selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, and substituted orunsubstituted 3- to 10-membered heterocyclyl; and

R^(30a) and R^(31a), R^(31a) and R^(32a) or R^(30a) and R^(32a) may,together with the atoms to which they are attached, form a substitutedor unsubstituted 5-, 6-, or 7-membered ring.

R¹⁰⁰ is selected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted3- to 10-membered heterocyclyl, —S(O)R³³, or —S(O)₂R³³; —C(O)R³³,—C(O)₂R³³;

R³³ is independently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₆₋₁₀ aryl, and substituted or unsubstituted 5- to10-membered heteroaryl.

R¹⁰¹ and R¹⁰² are each independently selected from the group consistingof hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₆₋₁₀ aryl, and substituted or unsubstituted 5- to10-membered heteroaryl;

R¹⁰¹ and R¹⁰² may, together with the nitrogen, form a substituted orunsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl;

r is 0, 1, or 2.

PREFERRED EMBODIMENTS

In one embodiment, any of formulae (I-CIII) is other thanN-(2-benzoyl-pyridin-3-yl)-4-isopropoxy-benzenesulfonamide.

In one embodiment, any of formulae (I-CIII), is other than formula CC:

where X¹⁴ is selected from the group consisting of —Cl, —NO₂, —OCH₃,—CH₃, —NHC(O)CH₃, and —CH₂CH₂-(phenyl);

R⁶⁵ is selected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₄ alkyl, and substituted or unsubstituted —SO₂(phenyl);and

R⁶⁰ is selected from the group consisting of —NR⁶¹CH₂CH₂OR⁶²,—NR⁶¹CH₂CH₂NR⁶³R⁶⁴, —NR⁶¹CH₂CH₂SR⁶²,

where R⁶¹ is selected from the group consisting of hydrogen andsubstituted or unsubstituted phenyl;

R⁶² is selected from the group consisting of substituted orunsubstituted phenyl, and substituted or unsubstituted C₁₋₄ alkyl; and

R⁶³ and R⁶⁴ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted phenyl, substituted or unsubstituted —SO₂(phenyl),—C(O)CH₃, —C(O)C(O)OH, and —C(O)₂C(CH₃)₃.

Preferred Ar and X Substituents

In one embodiment of formula (III), at least one of X², X³, X⁴, X⁵ andX⁶ is other than hydrogen; or at least two of X², X³, X⁴, X⁵ and X⁶ isother than hydrogen.

In one embodiment of formula (III), X³ is other than hydrogen.

In one embodiment of formula (III), X⁴ is other than hydrogen.

In one embodiment of formula (III), X⁴ is other than isopropoxy.

In one embodiment of formula (III), X⁴ is other than methyl.

In one embodiment of formula (III), X³ and X⁴ are other than hydrogen.

In one embodiment of formula (III), when X⁴ is isopropoxy, at least oneof X², X³, X⁵ and X⁶ is other than hydrogen.

In one embodiment of formula (III), X², X³, X⁴, X⁵ and X⁶ are eachindependently selected from the group consisting of hydrogen, halogen,—CN, —NO₂, —OR¹⁸, —C(O)R¹⁸, —SO₂R¹⁸, —NR¹⁸R¹⁹, unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted phenyl,unsubstituted or substituted 5- or 6-membered heteroaryl, andunsubstituted or substituted 5- or 6-membered heterocyclyl.

In one embodiment of formula (III), X², X³, X⁴, X⁵ and X⁶ are eachindependently selected from the group consisting of hydrogen, halogen,—CN, —NO₂, —OR¹⁸, —C(O)R¹⁸, —SO₂R¹⁸, —NR¹⁸R¹⁹, unsubstituted C₂₋₈ alkyl,substituted C₁₋₈ alkyl, unsubstituted or substituted phenyl,unsubstituted or substituted 5- or 6-membered heteroaryl, andunsubstituted or substituted 5- or 6-membered heterocyclyl.

In one embodiment of formula (III), X², X³, X⁴, X⁵ and X⁶ are eachindependently selected from the group consisting of hydrogen, halogen,—CN, —NO₂, —OR¹⁸ (but not isopropoxy), —C(O)R¹⁸, —SO₂R¹⁸, —NR¹⁸R¹⁹,unsubstituted or substituted C₁₋₈ alkyl, unsubstituted or substitutedphenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, andunsubstituted or substituted 5- or 6-membered heterocyclyl.

In one embodiment of formula (III), X², X³, X⁴, X⁵ and X⁶ are eachindependently selected from the group consisting of hydrogen, halogen,—CN, —NO₂, —OR¹⁸ (but not isopropoxy), —C(O)R¹⁸, —SO₂R¹⁸, —NR¹⁸R¹⁹,unsubstituted C₂₋₈ alkyl, substituted C₁₋₈ alkyl, unsubstituted orsubstituted phenyl, unsubstituted or substituted 5- or 6-memberedheteroaryl, and unsubstituted or substituted 5- or 6-memberedheterocyclyl.

In another embodiment of formula (III), X², X³, X⁴, X⁵ and X⁶ are eachindependently selected from the group consisting of: hydrogen, halogen,—CN, —NO₂, —OR¹⁸, —C(O)R¹⁸, —SO₂R¹⁸, —NR¹⁸R¹⁹, unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted phenyl,unsubstituted or substituted 5- or 6-membered heteroaryl, andunsubstituted or substituted 5- or 6-membered heterocyclyl; with theproviso that at least two of X², X³, X⁴, X⁵ and X⁶ are other thanhydrogen; or with the proviso that at least one of X², X³, X⁴, X⁵ and X⁶is other than hydrogen.

In another embodiment of formula (III), X², X³, X⁴, X⁵ and X⁶ are eachindependently selected from the group consisting of: hydrogen, halogen,—CN, —NO₂, —OR¹⁸, —C(O)R¹⁸, —SO₂R¹⁸, —NR¹⁸R¹⁹, unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted phenyl,unsubstituted or substituted 5- or 6-membered heteroaryl, andunsubstituted or substituted 5- or 6-membered heterocyclyl; with theproviso that at least two of X³, X⁴ and X⁵ are other than hydrogen; orwith the proviso at least one of X³, X⁴ and X⁵ is other than hydrogen.

In a further embodiment of formula (III), X², X³, X⁴, X⁵ and X⁶ are eachindependently selected from the group consisting of: hydrogen, halogen,—CN, —NO₂, —OR¹⁸, —C(O)R¹⁸, —SO₂R¹⁸, and —NR¹⁸R¹⁹; with the proviso thatat least three of X², X³, X⁴, X⁵ and X⁶ are other than hydrogen; or withthe proviso that at least two of X², X³, X⁴, X⁵ and X⁶ is other thanhydrogen; or with the proviso that at least one of X², X³, X⁴, X⁵ and X⁶is other than hydrogen.

In a further embodiment of formula (III), X², X³, X⁴, X⁵ and X⁶ are eachindependently selected from the group consisting of: hydrogen, halogen,unsubstituted or substituted C₁₋₈ alkyl, unsubstituted or substitutedphenyl, unsubstituted or substituted 5- or 6-membered heteroaryl, andunsubstituted or substituted 5- or 6-membered heterocyclyl; with theproviso that at least three of X², X³, X⁴, X⁵ and X⁶ are other thanhydrogen; or with the proviso that at least two of X², X³, X⁴, X⁵ and X⁶is other than hydrogen; or with the proviso that at least one of X², X³,X⁴, X⁵ and X⁶ is other than hydrogen.

In one embodiment of formula (III), X⁴ is selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, —CN, —C(O)R¹⁸, —CO₂R¹⁸, —C(O)NR¹⁸R¹⁹, —OC(O)R¹⁹,—OC(O)NR¹⁸R¹⁹, —NO₂, —NR¹⁸C(O)NR¹⁹R²⁰, —NR¹⁸R¹⁹, —NR¹⁸CO₂R¹⁹,—NR¹⁸S(O)₂R¹⁹, —SR¹⁸, —S(O)R¹⁸, —S(O)₂R¹⁸, —S(O)₂NR¹⁸R¹⁹, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-memberedheteroaryl, and substituted or unsubstituted 3- to 10-memberedheterocyclyl.

In one embodiment of formula (III), X⁴ is selected from the groupconsisting of halogen and —CH₃, and X³ is selected from the groupconsisting of halogen, —CH₃, —CF₃, —OCH₃, and —OCF₃.

In one embodiment of formula (III), when X², X³, X⁵ and X⁶ are hydrogen,X⁴ is other than —Cl, —NO₂, —OCH₃, —CH₃, —NHC(O)CH₃, or—CH₂CH₂-(phenyl).

In one embodiment of formulae (IV-C), X^(a) represents 1 to 5substituents each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,—CN, —C(O)R¹⁸, —CO₂R¹⁸, —C(O)NR¹⁸R¹⁹, —OC(O)R¹⁹, —OC(O)NR¹⁸R¹⁹, —NO₂,—NR¹⁸C(O)NR¹⁹R²⁰, —NR¹⁸R¹⁹, —NR¹⁸CO₂R¹⁹, —NR¹⁸S(O)₂R¹⁹, —SR¹⁸, —S(O)R¹⁸,—S(O)₂R¹⁸, —S(O)₂NR¹⁸R¹⁹, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, andsubstituted or unsubstituted 3- to 10-membered heterocyclyl.

In one embodiment of formulae (IV-C), X^(a) represents 1 to 5substituents each independently selected from the group consisting ofhalogen, —CN, —C(O)R²⁴, —CO₂R²⁴, —C(O)NR²⁴R²⁵, —OR²⁴, —OC(O)R²⁴,—OC(O)NR²⁴R²⁵, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)₂NR²⁴R²⁵, —NO₂,—NR²⁴R²⁵, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₆₋₁₀ aryl, and substituted or unsubstituted 5- to10-membered heteroaryl.

In one embodiment of formulae (IV-C), X^(a) represents 1 to 5substituents each independently selected from the group consisting ofhalogen, —CN, —C(O)R²⁴, —CO₂R²⁴, —C(O)NR²⁴R²⁵, —OR²⁴, —OC(O)R²⁴,—OC(O)NR²⁴R²⁵, —SR²⁴, —S(O)R²⁴, —S(O)₂R²⁴, —S(O)₂NR²⁴R²⁵, —NO₂,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₆₋₁₀ aryl, and substituted or unsubstituted 5- to10-membered heteroaryl.

In one embodiment of formulae (IV-C), when X^(a) is para alkyl, L isC(O), and Z¹ is phenyl, at least one other X^(a) substituent is present.

In one embodiment of formulae (IV-C), when X^(a) is para isopropoxy, Lis C(O), and Z¹ is phenyl, at least one other X^(a) substituent ispresent.

In one embodiment of formulae (IV-C), X^(a) represents 1 to 3substituents each independently selected from the group consisting ofhalogen, —CN, —NO₂, —OR²⁴, —C(O)R²⁴, —SO₂R²⁴, —NR²⁴R²⁵, unsubstituted orsubstituted C₁₋₈ alkyl, unsubstituted or substituted phenyl,unsubstituted or substituted 5- or 6-membered heteroaryl, andunsubstituted or substituted 5- or 6-membered heterocyclyl.

In one embodiment of formulae (IV-C), X^(a) represents 1 to 3substituents each independently selected from the group consisting ofhalogen, —CN, —NO₂, —OR²⁴ (but not isopropoxy), —C(O)R²⁴, —SO₂R²⁴,—NR²⁴R²⁵, unsubstituted or substituted C₁₋₈ alkyl, unsubstituted orsubstituted phenyl, unsubstituted or substituted 5- or 6-memberedheteroaryl, and unsubstituted or substituted 5- or 6-memberedheterocyclyl.

In one embodiment of formulae (IV-C), X^(a) represents two substituentseach independently selected from the group consisting of halogen, —CN,—NO₂, —OR²⁴, —C(O)R²⁴, —SO₂R²⁴, —NR²⁴R²⁵, unsubstituted or substitutedC₁₋₈ alkyl, unsubstituted or substituted phenyl, unsubstituted orsubstituted 5- or 6-membered heteroaryl, and unsubstituted orsubstituted 5- or 6-membered heterocyclyl.

In one embodiment of formulae (IV-C), X^(a) represents two substituentseach independently selected from the group consisting of halogen,methyl, —OCH₃, —OCF₃, and —CF₃.

In one embodiment of formulae (IV-C), X^(a) represents 1 to 2substituents each independently selected from the group consisting ofhalogen, —CN, and —CF₃.

In one embodiment of each of the formulae (IV-C), X⁴, X^(b), or at leastone of X^(a) or X is a substituted or unsubstituted 5- or 6-memberedheterocyclic ring, and the heterocycle is selected from the groupconsisting of pyrrolidine, piperidine, imidazolidine, pyrazolidine,butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane,phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine,thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran,pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, andtetrahydrothiophene. In one embodiment, X^(c), X², X³, X⁵, and X⁶ arehydrogen.

In one embodiment of each of the formulae (IV-C), X⁴, X^(b), or at leastone of X^(a) or X is a substituted or unsubstituted 5- or 6-memberedheteroaryl ring selected from the group consisting of pyridyl,pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, isothiazolyl, pyrazolyl,imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, pyrrolyl, and thiazolyl. In one embodiment,X^(c), X², X³, X⁵, and X⁶ are hydrogen.

In one embodiment of each of the formulae (IV-C), X⁴, X^(b), or at leastone of X^(a) or X is substituted or unsubstituted heterocyclic groupselected from the group consisting of pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, 1,3-dioxalanyl, thiomorpholinyl,thiomorpholinyl-S,S-dioxide, piperazinyl and pyranyl. In one embodiment,X^(c), X², X³, X⁵, and X⁶ are hydrogen.

In one embodiment of each of the formulae (IV-C), X⁴, X^(b), or at leastone of X^(a) or X is a substituted C₁₋₈ alkyl, where suitablesubstituents are as defined for formula (II). Preferably, thesubstituent is a substituted or unsubstituted heterocyclic group of theformula (AA) as defined above in “Abbreviations and Definitions”. Morepreferably, the substituent is selected from the group includingpyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam,valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide,piperidine, 1,4-dioxane, morpholine, thiomorpholine,thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran,pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, andtetrahydrothiophene. In one embodiment, X^(c), X², X³, X⁵, and X⁶ arehydrogen.

In one embodiment of each of the formulae (IV-C), X⁴, X^(b), or at leastone of X^(a) or X is a substituted C₁₋₈ alkyl, where suitablesubstituents are as defined for formula (II). In one preferredembodiment, the substituted C₁₋₈ alkyl is substituted with a 5- or6-membered heteroaryl selected from the group consisting of pyridyl,pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, isothiazolyl, pyrazolyl,imidazolyl, thienyl, furyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, pyrrolyl, and thiazolyl. More preferably, thesubstituted C₁₋₈ alkyl is substituted with oxazolyl. In one embodiment,X^(c), X², X³, X⁵, and X⁶ are hydrogen.

In one embodiment of each of the formulae (IV-C), a suitable substituentfor substituted C₁₋₈ alkyl (as X, X¹, X², X³, X⁴, X⁵, X^(a), X^(b), orX^(c)) can be selected from the group consisting of —CN, —OR¹⁸,—C(O)R¹⁸, —CO₂R¹⁸, —O(CO)R¹⁸, —SO₂R¹⁸ and halogen. In one embodiment,X^(c), X², X³, X⁵, and X⁶ are hydrogen.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is halogen,particularly chlorine.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is an unsubstitutedC₁₋₈ alkyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is an unsubstitutedC₂₋₈ alkyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is t-butyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is oxazolyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is trifluoromethoxy.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is —SO₂R¹⁸. In oneparticular embodiment, R¹⁸ is methyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is —OR¹⁸. In oneparticular embodiment, R¹⁸ is methyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is —SR¹⁸. In oneparticular embodiment, R¹⁸ is methyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is unsubstituted C₁₋₆alkyl (in particular methyl) or C₁₋₆ haloalkyl (in particular —CF₃).

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is substituted C₁₋₆alkyl (preferably not C₁₋₆ haloalkyl).

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is isopropyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is a cyano.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is a cyano, halogenor trifluoromethyl group.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is —C(Me)₂CH₂OH.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is —C(O)Me.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is —(CH₂)₂CO₂Me.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is isoamyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is 1,3-dioxalanyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is furyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is pyrazolyl.

In one embodiment of each of the formulae (IV-C), at least one of X^(a),X^(b), X^(c), X¹, X², X³, X⁴, X⁵ or at least one X is thienyl.

In one embodiment of formulae (IV-C), at least one of X^(b) and X^(c) isother than hydrogen.

In one embodiment of formulae (IV-C), X^(b) and X^(c) are eachindependently selected from the group consisting of hydrogen, halogen,—CN, —C(O)R^(24a), —CO₂R^(24a), —C(O)NR^(24a)R^(25a), —OR^(24a),—OC(O)R^(24a), —OC(O)NR^(24a)R^(25a), —SR^(24a), —S(O)R^(24a),—S(O)₂R^(24a), —S(O)₂NR^(24a)R^(25a), —NO₂, —NR^(24a)R^(25a),substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₆₋₁₀ aryl, and substituted or unsubstituted 5- to10-membered heteroaryl.

In one embodiment of formulae (IV-C), at least one of X^(b) and X^(c) isselected from the group consisting of halogen, —CN, —NO₂, —OR²⁴,—C(O)R²⁴, —SO₂R²⁴, —NR²⁴R²⁵, unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted phenyl, unsubstituted or substituted 5- or6-membered heteroaryl, and unsubstituted or substituted 5- or 6-memberedheterocyclyl.

In one embodiment of formulae (IV-C), at least one of X^(b) and X^(c) isselected from the group consisting of halogen, —CN, —NO₂, —OR²⁴ (but notisopropoxy), —C(O)R²⁴, —SO₂R²⁴, —NR²⁴R²⁵, unsubstituted or substitutedC₁₋₈ alkyl, unsubstituted or substituted phenyl, unsubstituted orsubstituted 5- or 6-membered heteroaryl, and unsubstituted orsubstituted 5- or 6-membered heterocyclyl.

In another embodiment of formulae (IV-C), X^(b) and X^(c) are both otherthan hydrogen.

In another embodiment of formulae (IV-C), when X^(b) is isopropoxy,X^(c) is other than hydrogen.

In another embodiment of formulae (IV-C), when X^(b) is methyl, X^(c) isother than hydrogen.

In another embodiment of formulae (IV-C), X^(b) and X^(c) are bothselected from the group consisting of halogen, —CN, —NO₂, —OR²⁴,—C(O)R²⁴, —SO₂R²⁴, —NR²⁴R²⁵, unsubstituted or substituted C₁₋₈ alkyl,unsubstituted or substituted phenyl, unsubstituted or substituted 5- or6-membered heteroaryl, and unsubstituted or substituted 5- or 6-memberedheterocyclyl.

In another embodiment of formulae (IV-C), X^(b) and X^(c), or any twooccurrences of X^(a) that are located adjacently to each other, can bejoined to form a substituted 5- or 6-membered substituted orunsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

In one embodiment of formulae (IV-C), at least one of X^(b) and X^(c) isselected from the group consisting of halogen, —CN, and —CF₃.

In one embodiment of formulae (IV-C), both X^(b) and X^(c) are selectedfrom the group consisting of halogen, —CN, and —CF₃.

In an additional embodiment of formulae (IV-C), one of X^(b), and X^(c)is halogen and one of X^(b) and X^(c) is selected from the groupconsisting of halogen, —CN, and —CF₃.

In an additional embodiment of formulae (IV-C), one of X^(b), and X^(c)is halogen and one of X^(b) and X^(c) is selected from the groupconsisting of halogen, —CN, —CH₃, and —CF₃.

In an additional embodiment of formulae (IV-C), one of X^(b), and X^(c)is hydrogen and one of X^(b) and X^(c) is selected from the groupconsisting of halogen, —CN, and —CF₃.

In an additional embodiment of formulae (IV-C), one of X^(b), and X^(c)is hydrogen and one of X^(b) and X^(c) is selected from the groupconsisting of halogen, —CN, —CH₃, and —CF₃.

In an additional embodiment of formulae (IV-C), X^(b) is selected fromthe group consisting of halogen and —CH₃, and X^(c) is selected from thegroup consisting of halogen, —CN, —CH₃, —OCH₃, —OCF₃ and —CF₃.

In an additional embodiment of formulae (IV-C), when X^(c) is hydrogen,X^(b) represents 1 to 5 substituents each independently selected fromthe group consisting of hydrogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, —CN, —C(O)R¹⁸, —CO₂R¹⁸, —C(O)NR¹⁸R¹⁹,—OC(O)R¹⁹, —OC(O)NR¹⁸R¹⁹, —NO₂, —NR¹⁸C(O)NR¹⁹R²⁰, —NR¹⁸R¹⁹, —NR¹⁸CO₂R¹⁹,—NR¹⁸S(O)₂R¹⁹, —SR¹⁸, —S(O)R¹⁸, —S(O)₂R¹⁸, —S(O)₂NR¹⁸R¹⁹, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-memberedheteroaryl, and substituted or unsubstituted 3- to 10-memberedheterocyclyl.

In an additional embodiment of formulae (IV-C), when X^(c) is hydrogen,X^(b) is other than —Cl, —NO₂, —OCH₃, —CH₃, —NHC(O)CH₃, or—CH₂CH₂-(phenyl).

In an additional embodiment of formulae (IV-C), X^(a) represents 2substituents, one of which is halogen and the other of which is selectedfrom the group consisting of halogen, —CN, and —CF₃.

In an additional embodiment of formulae (IV-C), X^(a) represents 2substituents, where one occurrence of X^(a) is halogen and oneoccurrence of X^(a) is located para to the sulfonamido bond.

In an additional embodiment of formulae (IV-C), at least one of oneoccurrence of X^(a) or alternatively one of X^(b) or X^(c) is —CN.

In another embodiment of formulae (IV-C), at least one of one occurrenceof X^(a) or alternatively one of X^(b) or X^(c) is halogen.

In an additional embodiment of formulae (IV-C), at least one of oneoccurrence of X^(a) or alternatively one of X^(b) or X^(c) is —CF₃.

In an additional embodiment of formulae (IV-C), at least one of oneoccurrence of X^(a), or one of X^(b) and X^(c), is selected from thegroup consisting of:

In one embodiment of the formulae (I, II, XCV-C), Ar is selected fromthe group consisting of substituted or unsubstituted C₆₋₁₀ aryl andsubstituted or unsubstituted 5- to 10-membered heteroaryl, with theproviso that Ar is other than para-isopropoxy phenyl.

In one embodiment of the formulae (I, II, XCV-C), Ar is selected fromthe group consisting of:

Preferred R¹ Substituents

In one embodiment of formula (I and II), R¹ is hydrogen.

In one embodiment of formula (I and II), R¹ is methyl.

In one embodiment of formula (I and II), R¹ is selected from the groupconsisting of hydrogen, unsubstituted C₂₋₈ alkyl, substituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, and substituted or unsubstituted 3- to10-membered heterocyclyl.

In one embodiment of formula (I and II), R¹ is selected from the groupconsisting of hydrogen, substituted or unsubstituted C₂₋₆ alkenyl,substituted or unsubstituted C₂₋₆ alkynyl, and substituted orunsubstituted 3- to 10-membered heterocyclyl.

In one embodiment of formula (I and II), R¹ is selected from the groupconsisting of unsubstituted C₂₋₈ alkyl, substituted, C₁₋₈ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl.

In one embodiment of formula (I and II), R¹ is substituted orunsubstituted 3- to 10-membered heterocyclyl.

In one embodiment of formula (I and II), R¹ is selected from the groupconsisting of substituted or unsubstituted C₅₋₈ alkyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,and substituted or unsubstituted 3- to 10-membered heterocyclyl;

In one embodiment of formula (I and II), R¹ is other than hydrogen, andsubstituted or unsubstituted C₁₋₄ alkyl.

Preferred Y and R² Substituents

In one embodiment of formula (I), Y¹, Y² and Y³ are —CR^(2a)—,—CR^(2b)—, and —CR^(2c)— respectively, where R^(2a), R^(2b), and R^(2c)are each hydrogen.

In one embodiment of formula (I), Y¹, Y² and Y³ are —CR^(2a)—,—CR^(2b)—, and —CR^(2c)— respectively, where 1 to 3 of R^(2a), R^(2b),and R^(2c) are other than hydrogen.

In one embodiment of formula (I), Y¹, Y² and Y³ are —CR^(2a)—,—CR^(2b)—, and —CR^(2c)— respectively and R^(2a), R^(2b), and R^(2c) areeach independently selected from the group consisting of halogen,—CO₂R³, —OR³, and substituted or unsubstituted C₁₋₈ alkyl, where 1 to 3of R^(2a), R^(2b), and R^(2c) are other than hydrogen.

In one embodiment of formula (I), Y¹, Y² and Y³ are —CR^(2a)—,—CR^(2b)—, and —CR^(2c)— respectively and R^(2a), R^(2b), and R^(2c) areeach independently selected from the group consisting of hydrogen,fluorine, chlorine, and bromine, where 1 to 2 of R^(2a), R^(2b), andR^(2c) are other than hydrogen.

In one embodiment of formula (I), at least one of Y¹, Y² and Y³ is —N—or —N⁺(O)⁻—.

In one embodiment of formula (I), only one of Y¹, Y² and Y³ is —N— or—N⁺(O)⁻—.

In one embodiment of formula (II), Y⁵, Y⁶, and Y⁷ are each independentlyselected from the group consisting of hydrogen, halogen, —CO₂R³, —OR³,and substituted or unsubstituted C₁₋₈ alkyl, where 1 to 2 of Y⁵, Y⁶, andY⁷ are other than hydrogen.

In one embodiment of formula (II), Y⁵, Y⁶, and Y⁷ are each independentlyselected from the group consisting of hydrogen, fluorine, chlorine, andbromine, where 1 to 2 of Y⁵, Y⁶, and Y⁷ are other than hydrogen.

In another embodiment of formula (II), at least one of Y⁵, Y⁶ and Y⁷ isother than hydrogen; preferably Y⁶ is halogen.

In another embodiment of formula (II), Y⁵ and Y⁷ are hydrogen and Y⁶ ishalogen.

In another embodiment of formula (II), Y⁵ and Y⁷ are hydrogen and Y⁶ ischloro.

In one embodiment of formula (III), Y⁸, Y⁹, and Y¹⁰ are eachindependently selected from the group consisting of hydrogen, halogen,—CO₂R³, —OR³, and substituted or unsubstituted C₁₋₈ alkyl, where 1 to 2of Y⁸, Y⁹, and Y¹⁰ are other than hydrogen.

In one embodiment of formula (III), Y⁸, Y⁹, and Y¹⁰ are eachindependently selected from the group consisting of hydrogen, fluorine,chlorine, and bromine, where 1 to 2 of Y⁸, Y⁹, and Y¹⁰ are other thanhydrogen.

In one embodiment of formula (III), at least one of Y⁸, Y⁹ and Y¹⁰ isother than hydrogen; preferably Y⁹ is other than hydrogen.

In another embodiment of formula (III), at least two of Y⁸, Y⁹ and Y¹⁰are other than hydrogen.

In a further embodiment of formula (III), Y⁸ and Y¹⁰ are hydrogen and Y⁹is halogen.

In a further embodiment of formula (III), Y⁸ and Y¹⁰ are hydrogen and Y⁹is chloro.

In one embodiment of formulae (IV-C), Y^(b) or at least one occurrenceof Y^(a) is other than hydrogen.

In one embodiment of formulae (IV-C), Y^(a) represents zero substituentsand Y^(b) is hydrogen.

In one embodiment of formulae (IV-C), Y^(a) represents zero substituentsand Y^(b) is other than hydrogen.

In one embodiment of formulae (IV-C), Y^(b) and each occurrence of Y^(a)are selected from the group consisting of halogen, —C(O)R²⁷, —OR²⁷, andsubstituted or unsubstituted C₁₋₈ alkyl.

In one embodiment of formulae (IV-C), Y^(b) and each occurrence of Y^(a)are selected from the group consisting of halogen, fluorine, chlorineand bromine.

In one embodiment of formulae (IV-C), Y^(b) and each occurrence of Y^(a)are selected from the group consisting of fluorine, chlorine andbromine.

In one embodiment of formulae (IV-C), Y^(b) and each occurrence of Y^(a)are selected from the group consisting of chlorine and hydrogen, whereone of Y^(a) and Y^(b) is hydrogen and one of Y^(a) and Y^(b) ischlorine.

Preferred L Substituents

In one embodiment of formula (I-C), L is a bond.

In one embodiment of formula (I-C), L is —C(O)—.

In one embodiment of formula (I-C), L is —S—.

In one embodiment of formula (I-C), L is —O—.

In one embodiment of formula (I-C), L is —S(O)—.

In one embodiment of formula (I-C), L is —S(O)₂—.

In one embodiment of formula (I-C), L is —CR⁶R⁷—.

In one embodiment of any of formulae (I-C) where L is —CR⁶R⁷—, R⁶ ishydrogen, halogen, —OR⁹ (where R³ is as defined in formula (I) andpreferably is hydrogen or C₁₋₄ alkyl), substituted or unsubstituted C₂₋₄alkyl, or substituted or unsubstituted C₂₋₄ alkenyl.

In one embodiment of any of formulae (I-C) where L is —CR⁶R⁷—, R⁷ ishydrogen, halogen, or —OR⁹ (where R⁹ is as defined in formula (I) andpreferably is hydrogen or C₁₋₄ alkyl).

In one embodiment of any of formulae (I-C) where L is —CR⁶R⁷—, one of R⁶and R⁷ is other than hydrogen.

In one embodiment of any of formulae (I-C) where L is —CR⁶R⁷—, R⁶ and R⁷are both halogen, and more preferably, are both fluorine.

In one embodiment of any of formulae (I-C) where L is —CR⁶R⁷—, R⁶ ishydrogen and R⁷ is —OR⁹ (where R⁹ is as defined in formula (I) and ispreferably hydrogen or C₁₋₄ alkyl).

In one embodiment of any of formulae (I-C) where L is —CR⁶R⁷—, R⁶ and R⁷are both —OR⁹ (where R⁹ is as defined in formula (I)) and where both R⁹groups are combined together with the atoms to which they are attachedto form a 5-7 membered heterocyclic acetal ring system.

In one embodiment of any of formulae (I-C) where L is —CR⁶R⁷—, R⁶ isC₁₋₄ alkyl or C₂₋₄ alkenyl and R⁷ is —OR⁹ (where R⁹ is as defined informula (I) and is preferably hydrogen or C₁₋₄ alkyl).

In one embodiment of formula (I-C), L is —NR⁸—, R⁸ is selected from thegroup consisting of hydrogen, C(O)R¹², S(O)₂R¹², CO₂R¹², substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted 3- to 10-memberedheterocyclyl, substituted or unsubstituted C₂₋₆ alkenyl, and substitutedor unsubstituted C₂₋₆ alkynyl.

In one embodiment, in each of the formulae I-C where L is —NR⁸—, R⁸ ishydrogen or —C(O)Me.

In one embodiment, in each of the formulae I-C where L is —NR⁸—, R⁸ ishydrogen or —C(O)Me.

In one preferred embodiment of any of formulae (I-C) where L is —NR⁸—,R⁸ is hydrogen, —S(O)₂R¹² or —C(O)R¹².

In one embodiment of formula (I-C), L is —NR⁸C(O)—.

In one embodiment of formula (I-C), L is —C(O)NR⁸—.

Preferred Z¹ Groups and Substituents

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedaryl.

In one embodiment of formulae (I-C), Z¹ is substituted aryl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedheteroaryl.

In one embodiment of formulae (I-C), Z¹ is substituted heteroaryl.

In one embodiment of formulae (I-C), Z¹ is unsubstituted heteroaryl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedheterocyclyl.

In one embodiment of formulae (I-C), Z¹ is —NR^(35b)R^(36b), where:

R^(35b) and R^(36b) are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, substituted or unsubstituted 3- to 10-memberedheterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted(C₁₋₄ alkyl)-(C₆₋₁₀ aryl), and substituted or unsubstituted (C₁₋₄alkyl)-(5- to 10-membered heteroaryl);

R^(35b) and R^(36b) may, together with the nitrogen, form a substitutedor unsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl.

In one embodiment of formulae (I-C), Z¹ is —NR¹³R¹⁴, where R¹³ and R¹⁴are each independently selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-memberedheteroaryl, substituted or unsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀ aryl), andsubstituted or unsubstituted (C₁₋₄ alkyl)-(5- to 10-memberedheteroaryl);

R¹³ and R¹⁴ may, together with the nitrogen, form a substituted orunsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl.

In one embodiment of formulae (I-C), Z¹ is other than

In one embodiment of formulae (I-C), Z¹ is one of the following formulae(CI and CII):

where Z² represents 0 to 5 substituents selected from the groupconsisting of halogen, —CN, —C(O)R³⁴, —CO₂R³⁴, —C(O)NR³⁴R³⁶, —OR³⁴,—OC(O)R³⁴, —OC(O)NR³⁴R³⁶, —SR³⁴, —S(O)R³⁴, —S(O)₂R³⁴, —S(O)₂NR³⁴R³⁶,—NO₂, —NR³⁴R³⁵, —NR³⁴C(O)R³⁵, —NR³⁴C(O)₂R³⁵, —NR³⁴S(O)₂R³⁵,—NR³⁴C(O)NR³⁵R³⁶, oxo (═O or —O⁻), substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, substituted or unsubstituted 3- to10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, substitutedor unsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀ aryl), and substituted orunsubstituted (C₁₋₄ alkyl)-(5- to 10-membered heteroaryl);

R³⁴, R³⁵, and R³⁶ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl;

Z³, Z⁴, Z⁵, Z⁶ and Z⁷ are each independently selected from the groupconsisting of —CR^(2a)—, —N—, and —N⁺(O)⁻—;

each R^(2a) is independently selected from the group consisting ofhydrogen, halogen, —CN, —C(O)R³, —CO₂R³, —C(O)NR³R⁴, —OR³, —OC(O)R³,—OC(O)NR³R⁴, —SR³, —S(O)R³, —S(O)₂R³, —S(O)₂NR³R⁴, —NO₂, —NR³R⁴,—NR³C(O)R⁴, —NR³C(O)OR⁴, —NR³S(O)₂R⁴, —NR³C(O)NR⁴R⁵, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted C₆₋₁₀ aryl,and substituted or unsubstituted 5- to 10-membered heteroaryl;

R³, R⁴, and R⁵ are each independently selected from the group consistingof hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl, and substituted or unsubstituted 3- to10-membered heterocyclyl;

R³ and R⁴, R⁴ and R⁵ or R³ and R⁵ may, together with the atoms to whichthey are attached, form a substituted or unsubstituted 5-, 6-, or7-membered ring.

In one embodiment of formulae (CI and CII), Z³, Z⁴, Z⁵, Z⁶ and Z⁷ are—CH—.

In one embodiment of formulae (CI and CII), at least one of Z³, Z⁴, Z⁵,Z⁶ and Z⁷ is —N—, or —N⁺(O)⁻—.

In one embodiment of formulae (CI and CII), at least one of Z³, Z⁴, Z⁵,Z⁶ and Z⁷ is —N⁺(O)⁻—.

In one embodiment of formulae (CI and CII), at least one of Z³, Z⁴, Z⁵,Z⁶ and Z⁷ is —N—.

In one embodiment of formulae (CI and CII), Ar is substituted orunsubstituted C₆₋₁₀ aryl and one of Z³, Z⁴, Z⁵, Z⁶ and Z⁷ is —N—, or

In one embodiment of formulae (CI and CII), Ar is substituted orunsubstituted C₆₋₁₀ aryl, L is —O—, —S—, —S(O)— or S(O)₂— and one of Z³,Z⁴, Z⁵ and Z⁶ is —N—, or —N⁺(O)⁻—.

In one embodiment of formulae (CI and CII), Ar is substituted phenyl, Lis —O—, —S—, —S(O)— or S(O)₂— and one of Z³, Z⁴, Z⁵ and Z⁶ is —N—, or—N⁺(O)⁻—.

In one embodiment of formulae (CI and CII), Ar is substituted orunsubstituted C₆₋₁₀ aryl, L is —CR⁵R⁶—, —NR⁷—, —C(O)— and one of Z³, Z⁴,Z⁵ and Z⁶ is —N—, or —N⁺(O)⁻—.

In one embodiment of formulae (CI and CII), Ar is substituted phenyl, Lis —CR⁵R⁶—, —NR⁷—, —C(O)— and one of Z³, Z⁴, Z⁵ and Z⁶ is —N—, or—N⁺(O)⁻—.

In one embodiment of formulae (I-C), Z¹ is one of the following formulae(CIII and CIV):

where Z⁸, Z¹⁰, Z¹¹, Z¹³, Z¹⁴ and Z¹⁵ are each independently selectedfrom the group consisting of —CR³⁷—, —N—, and —N⁺(O)⁻—;

R³⁷ represents 0 to 4 substituents selected from the group consisting ofhalogen, —CN, —C(O)R³⁸, —CO₂R³⁸, —C(O)NR³⁸R³⁹, —OR³⁸, —OC(O)R³⁸,—OC(O)NR³⁸R³⁹, —SR³⁸, —S(O)R³⁹, —S(O)₂R³⁸, —S(O)₂NR³⁸R³⁹, —NO₂,—NR³⁸R³⁹, —NR³⁸C(O)R³⁹, —NR³⁸C(O)₂R³⁹, —NR³⁸S(O)₂R³⁹, —NR³⁸C(O)NR³⁹R⁴⁰,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-memberedheteroaryl, substituted or unsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀ aryl), andsubstituted or unsubstituted (C₁₋₄ alkyl)-(5- to 10-memberedheteroaryl);

R³⁸, R³⁹, and R⁴⁰ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl;

Z⁹ and Z¹² are each independently selected from the group consisting of—O—, —S—, —NR⁴¹—, and —N⁺(O)⁻—;

R⁴¹ is selected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted 3- to 10-memberedheterocyclyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, andsubstituted or unsubstituted 5- to 10-membered heteroaryl.

In one embodiment of formulae (CIII and CIV), one of Z⁸, Z¹⁰ and Z¹¹ is—N— or —N⁻—O⁺ or one of Z¹³, Z¹⁴ and Z¹⁵ is —N— or —N⁻—O⁺.

In one embodiment of formulae (CIII and CIV), at least one of Z⁸, Z¹⁰and Z¹¹ is —N— or —N⁻—O⁺ or one of Z¹³, Z¹⁴ and Z¹⁵ is —N— or —N⁻—O⁺.

In one embodiment of formulae (I-C), Z¹ is selected from the formulae(CV-CXXI):

where,

A is selected from the group consisting of —CH—, —CZ¹⁶—, —N—, and—N⁺(O)⁻—;

each occurrence of Z¹⁶ is independently selected from the groupconsisting of halogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, —CN, oxo (═O or —O⁻), —NO₂, —OR⁴², —OC(O)R⁴², —CO₂R⁴²,—C(O)R⁴², —C(O)NR⁴²R⁴³, —OC(O)NR⁴²R⁴³, —NR⁴²C(O)R⁴³, —NR⁴²C(O)NR⁴³R⁴⁴,—NR⁴²R⁴³, —NR⁴²CO₂R⁴³, —SR⁴², —S(O)R⁴², —S(O)₂R⁴², —S(O)₂NR⁴²R⁴³,—NR⁴²S(O)₂R⁴³, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted (C₁₋₄alkyl)-(C₆₋₁₀ aryl), and substituted or unsubstituted (C₁₋₄ alkyl)-(5-to 10-membered heteroaryl); or where two or more A are CZ¹⁶, then theZ¹⁶ substituents together can form a carbocyclic or heterocyclic ring;

R⁴², R⁴³ and R⁴⁴ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl;

E is selected from the group consisting of —CH—, —CZ¹⁷—, —N—, and—N⁺(O)⁻—;

each occurrence of Z¹⁷ is independently selected from the groupconsisting of halogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted C₂₋₈ alkenyl, substituted or unsubstitutedC₂₋₈ alkynyl, —CN, oxo (═O or —O⁻), —NO₂, —OR⁴⁴, —OC(O)R⁴⁴, —CO₂R⁴⁴,—C(O)R⁴⁴, —C(O)NR⁴⁴R⁴⁵, —OC(O)NR⁴⁴R⁴⁵, —NR⁴⁴C(O)R⁴⁵, —NR⁴⁴C(O)NR⁴⁵R⁴⁶,—NR⁴⁴R⁴⁵, —NR⁴⁴CO₂R⁴⁵, —SR⁴⁴, —S(O)R⁴⁴, —S(O)₂R⁴⁴, —S(O)₂NR⁴⁴R⁴⁵,—NR⁴⁴S(O)₂R⁴⁵, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted3- to 10-membered heterocyclyl, substituted or unsubstituted (C₁₋₄alkyl)-(C₆₋₁₀ aryl), and substituted or unsubstituted (C₁₋₄ alkyl)-(5-to 10-membered heteroaryl); or where two or more E are CZ¹⁷, then theZ¹⁷ substituents together can form a carbocyclic or heterocyclic ring;

R⁴⁴, R⁴⁵ and R⁴⁶ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl;

G is selected from the group consisting of —O—, —S—, and —NR⁴⁷—;

R⁴⁷ is selected from the group consisting of hydrogen, substituted orunsubstituted C₁₋₈ alkyl, substituted or unsubstituted 3- to 10-memberedheterocyclyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, andsubstituted or unsubstituted 5- to 10-membered heteroaryl; or where G is—NR⁴⁷—, A is —CZ¹⁶— and E is —CZ¹⁷—, two the R⁴⁷, Z¹⁶, and Z¹⁷substituents together can form a carbocyclic or heterocyclic ring.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstituted5- to 10-membered heteroaryl.

In one embodiment of formulae (I-C), Z¹ is substituted 5- or 6-memberedheteroaryl.

In one embodiment of formulae (I-C), Z¹ is unsubstituted 5- or6-membered heteroaryl.

In one embodiment of formulae (I-C), Z¹ is substituted 9- or 10-memberedheteroaryl.

In one embodiment of formulae (I-C), Z¹ is unsubstituted 9- or10-membered heteroaryl.

In one embodiment of formulae (I-C), Z¹ is substituted 5- to 10-memberedheteroaryl, wherein one substituent is located ortho- to one of theheteroatoms in the ring.

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of substituted or unsubstituted 5- or 6-membered heteroarylwith 1 to 2 nitrogen atoms and with 0 or 2 substituents independentlyselected from the group consisting of halogen, unsubstituted orsubstituted C₁₋₈ alkyl, oxo (═O or —O⁻), —CN, —NO₂, —OR⁴⁸, —C(O)R⁴⁸,—C(O)NR⁴⁸R⁴⁹, —NR⁴⁸C(O)R⁴⁹, —NR⁴⁸R⁴⁹, —SR⁴⁸, —S(O)R⁴⁸, S(O)₂R⁴⁸,—SO₂NR⁴⁸R⁴⁹, —NR⁴⁸SO₂R⁴⁹, unsubstituted or substituted 5- to 6-memberedheteroaryl, unsubstituted or substituted 3- to 10-membered heterocyclyl,substituted or unsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀ aryl), and substitutedor unsubstituted (C₁₋₄ alkyl)-(5- to 10-membered heteroaryl);

R⁴⁸ and R⁴⁹ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl.

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of substituted or unsubstituted 5- or 6-membered heteroarylwith 1 to 2 nitrogen atoms and with 0 or 2 substituents eachindependently selected from the group consisting of halogen, substitutedor unsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, —CN, oxo (═O or —O⁻), —NO₂,—OR⁴⁴, —OC(O)R⁴⁴, —CO₂R⁴⁴, —C(O)R⁴⁴, —C(O)NR⁴⁴R⁴⁵, —OC(O)NR⁴⁴R⁴⁵,—NR⁴⁴C(O)R⁴⁵, —NR⁴⁴C(O)NR⁴⁵R⁴⁶, —NR⁴⁴R⁴⁵, —NR⁴⁴CO₂R⁴⁵, —SR⁴⁴, —S(O)R⁴⁴,—S(O)₂R⁴⁴, —S(O)₂NR⁴⁴R⁴⁵, —NR⁴⁴S(O)₂R⁴⁵, substituted or unsubstitutedC₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryland substituted or unsubstituted 3- to 10-membered heterocyclyl;

R⁴⁴, R⁴⁵ and R⁴⁶ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl;

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of substituted or unsubstituted 5- or 6-membered heteroarylwith 1 to 2 nitrogen atoms and with 0 or 2 substituents independentlyselected from the group consisting of substituted or unsubstituted C₂₋₈alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, —CO₂R^(44a),—OC(O)NR^(44a)R^(45a), —NR^(44a)C(O)NR^(45a)R^(46a), —NR^(44a)CO₂R^(45a)and substituted or unsubstituted C₆₋₁₀ aryl;

R^(44a), R^(45a) and R^(46a) are each independently selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl;

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of substituted or unsubstituted 9- or 10-membered heteroarylwith 1 to 2 nitrogen atoms and with 0 or 2 substituents independentlyselected from the group consisting of halogen, unsubstituted orsubstituted C₁₋₈ alkyl, oxo (═O or —O⁻), —CN, —NO₂, —OR⁴⁸, —C(O)R⁴⁸,—C(O)NR⁴⁸R⁴⁹, —NR⁴⁸C(O)R⁴⁹, —NR⁴⁸R⁴⁹, —SR⁴⁸, —S(O)R⁴⁸, S(O)₂R⁴⁸,—SO₂NR⁴⁸R⁴⁹, —NR⁴⁸SO₂R⁴⁹, unsubstituted or substituted 5- to 6-memberedheteroaryl, unsubstituted or substituted 3- to 10-membered heterocyclyl,and substituted or unsubstituted (C₁₋₄ alkyl)-(5- to 10-memberedheteroaryl);

R⁴⁸ and R⁴⁹ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl.

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of substituted or unsubstituted 9- or 10-membered heteroarylwith 1 to 2 nitrogen atoms and with 0 or 2 substituents eachindependently selected from the group consisting of halogen, substitutedor unsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, —CN, oxo (═O or —O⁻), —NO₂,—OR⁴⁴, —OC(O)R⁴⁴, —CO₂R⁴⁴, —C(O)R⁴⁴, —C(O)NR⁴⁴R⁴⁵, —OC(O)NR⁴⁴R⁴⁵,—NR⁴⁴C(O)R⁴⁵, —NR⁴⁴C(O)NR⁴⁵R⁴⁶, —NR⁴⁴R⁴⁵, —NR⁴⁴CO₂R⁴⁵, —SR⁴⁴, —S(O)R⁴⁴,—S(O)₂R⁴⁴, —S(O)₂NR⁴⁴R⁴⁵, —NR⁴⁴S(O)₂R⁴⁵, substituted or unsubstitutedC₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryland substituted or unsubstituted 3- to 10-membered heterocyclyl;

R⁴⁴, R⁴⁵ and R⁴⁶ are each independently selected from the groupconsisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl;

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of substituted or unsubstituted 9- or 10-membered heteroarylwith 1 to 2 nitrogen atoms and with 0 or 2 substituents independentlyselected from the group consisting of substituted or unsubstituted C₂₋₈alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, —CO₂R^(44a),—OC(O)NR^(44a)R^(45a), —NR^(44a)C(O)NR^(45a)R^(46a), —NR^(44a)CO₂R^(45a)and substituted or unsubstituted C₆₋₁₀ aryl;

R^(44a), R^(45a) and R^(46a) are each independently selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl;

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of substituted or unsubstituted pyridyl, substituted orunsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, andsubstituted or unsubstituted pyrazinyl, where the nitrogen atoms mayalso be —N⁺(O)⁻—.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstituted5- to 10-membered heteroaryl, where the heteroaryl group contains onlyone nitrogen.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstituted5- or 6-membered heteroaryl, where the heteroaryl group contains onlyone nitrogen.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstituted9- or 10-membered heteroaryl, where the heteroaryl group contains onlyone nitrogen.

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of isothiazolyl, pyrazolyl, imidazolyl, thienyl, furyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,pyrrolyl, thiazolyl, where each of these groups may be substituted orunsubstituted.

In one embodiments of formulae (I-C), Z¹ is substituted pyrazolyl with 0to 3 substituents, substituted imidazolyl with 0 to 3 substituents,substituted tetrazolyl with 0 to 3 substituents, or substituted oxazolylwith 0 to 3 substituents.

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of pyridyl, pyrrolyl, pyridazinyl, pyrazinyl, pyrimidinyl,triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl,benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,pyrrolopyirdinyl, imidazopyridinyl, benzothiazolyl, benzofuranyl,benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl,indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl andthienyl, where each of these groups may be substituted or unsubstituted.

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl,quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl,benzoxazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl,benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyridyl,imidazopyridyl, oxazolopyridyl, isoxaxolopyridyl, thiazolopyridyl,isothiazolopyridyl, benzothiazolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiadiazolyl, pyrrolyl, thiazolyl, furyl and thienyl, where each ofthese groups may be substituted or unsubstituted.

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzoxazolyl, benzoxazolyl, benzisoxazolyl,isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, pyrazolopyridyl,imidazopyridyl, oxazolopyridyl, isoxaxolopyridyl, thiazolopyridyl,isothiazolopyridyl, pyridopyridazinyl, pyridopyrimidinyl,pyridopyrazinyl, benzothiazolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, indazolyl, and pteridinyl where each of thesegroups may be substituted or unsubstituted.

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of pyrazolopyridyl, imidazopyridyl, oxazolopyridyl,isoxaxolopyridyl, thiazolopyridyl, isothiazolopyridyl,pyridopyridazinyl, pyridopyrimidinyl, and pyridopyrazinyl where each ofthese groups may be substituted or unsubstituted.

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of pyrazolopyridyl, isoxaxolopyridyl, and isothiazolopyridyl,where each of these groups may be substituted or unsubstituted.

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of 4-azaindolyl, 5-azaindolyl, 6-azaindolyl, 6-azaindolyl,4-azaindazolyl, 5-azaindazolyl, 6-azaindazolyl, 7-azaindazolyl, whereeach of these groups may be substituted or unsubstituted.

In one embodiment of formulae (I-C), Z¹ is a substituted orunsubstituted 3- to 10-membered heterocyclyl.

In one embodiment of formulae (I-C), Z¹ is unsubstituted or substituted4- to 7-membered heterocyclyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstituted3- to 10-membered heterocyclyl, where the 3- to 10-membered heterocyclylis selected from the group consisting of pyrrolidine, piperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, phthalimide, piperidine, 1,4-dioxane,morpholine, thiomorpholine, thiomorpholine-S,S-dioxide, piperazine,pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, andtetrahydrothiophene.

In one embodiment of formulae (I-C), Z¹ is substituted morpholinyl withfrom 0 to 3 substituents, substituted pyrrolidinyl with from 0 to 3substituents, substituted piperidinyl with from 0 to 3 substituents,substituted thiomorpholine-S,S-dioxide with from 0 to 3 substituents, orsubstituted piperazinyl with from 0 to 3 substituents.

In one embodiment of formulae (I-C), when Z¹ is substituted Z¹ may besubstituted with chlorine, fluorine, unsubstituted or substituted C₁₋₈alkyl, oxo (═O or —O⁻), —CN, —NO₂, —OMe, —C(O)Me, —CONH₂, —CONHMe,—CONMe₂, —NHC(O)Me, —NH₂, —NHMe, —NMe₂, —SMe, —S(O)Me, —S(O)₂Me,—NHSO₂Me, morpholinyl, —CH₂OH, —CH₂OMe, —CH₂NH₂, —CH₂NHMe, or —CH₂NMe₂.

In one embodiment of formulae (I-C), when Z¹ is substituted, Z¹ may besubstituted with substituted or unsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀ aryl),substituted or unsubstituted (C₁₋₄ alkyl)-(5- to 10-memberedheteroaryl).

In one embodiment of formulae (I-C), when Z¹ is substituted Z¹ may besubstituted with chlorine, fluorine, methyl, oxo (═O or —O⁻), —CN, —OMe.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstituted2-pyridyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstituted2-pyridyl-N-oxide.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstituted3-pyridyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstituted3-pyridyl-N-oxide.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstituted4-pyridyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstituted4-pyridyl-N-oxide.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedpyrazolyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedimidazolyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedtetrazolyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedoxazolyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedmorpholinyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedpyrrolidinyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedpiperidinyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedthiomorpholinyl-S, S-dioxide.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedpyridopyridazinyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedphthalazinyl.

In one embodiment of formulae (I-C), Z¹ is substituted or unsubstitutedpyrazolopyridyl.

In one embodiment of formulae (I-C), Z¹ is not substituted.

In one embodiment of formula (I-C), Z¹ is substituted by —CH₃ or oxo (═Oor —O⁻).

In one embodiment of formula (I-C), Z¹ is substituted by —CH₃ and oxo(═O or —O⁻).

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of:

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of:

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of:

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of:

In one embodiment of formulae (I-C), Z¹ is selected from the groupconsisting of:

In one embodiment of formulae (I-C), Z¹ may have one or moresubstituents selected from the group consisting of:

In one embodiment of formula (I-C), Z¹ has 0 to 3 substituents, each ofwhich are independently selected from the group consisting of —CH₃ andoxo (═O or —O⁻).

In one embodiment of formulae (I-C), Z^(a) and/or Z^(b) is locatedortho- to one of the heteroatoms in the ring.

In one embodiment of formulae (I-C), Z^(a) and Z^(b) are eachindependently selected from the group consisting of halogen,unsubstituted or substituted C₁₋₈ alkyl, oxo (═O or —O⁻), —CN, —NO₂,—OR⁵⁰, —C(O)R⁵⁰, —CONR⁵⁰R⁵¹, —NR⁵⁰C(O)R⁵¹, —NR⁵⁰R⁵¹, —SR⁵⁰, —S(O)R⁵⁰,—S(O)₂R⁵⁰, —SO₂NR⁵⁰R⁵¹, —NR⁵⁰SO₂R⁵¹, unsubstituted or substituted 5- to6-membered heteroaryl, unsubstituted or substituted 4- to 7-memberedheterocyclyl, substituted or unsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀ aryl),and substituted or unsubstituted (C₁₋₄ alkyl)-(5- to 10-memberedheteroaryl);

R⁵⁰ and R⁵¹ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl.

In one embodiment of formulae (I-C), Z^(a) and Z^(b) are eachindependently selected from the group consisting of halogen, substitutedor unsubstituted C₁₋₈ alkyl, substituted or unsubstituted C₂₋₈ alkenyl,substituted or unsubstituted C₂₋₈ alkynyl, —CN, oxo (═O or —O⁻), —NO₂,—OR^(50a), —OC(O)R^(50a), —CO₂R^(50a), —C(O)R^(50a),—C(O)NR^(50a)R^(51a), —OC(O)NR^(50a)R^(51a), —NR^(50a)C(O)R^(51a),—NR^(50a)C(O)NR^(51a)R^(51b), —NR^(50a)R^(51a), —NR^(50a)CO₂R^(51a),—SR^(50a), —S(O)R^(50a), —S(O)₂R^(50a), —S(O)₂NR^(50a)R^(51a),—NR^(50a)S(O)₂R^(51a), substituted or unsubstituted C₆₋₁₀ aryl,substituted or unsubstituted 5- to 10-membered heteroaryl, substitutedor unsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀ aryl), and substituted orunsubstituted (C₁₋₄ alkyl)-(5- to 10-membered heteroaryl);

R^(50a), R^(51a) and R^(51b) are each independently selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl.

In one embodiment of formulae (I-C), Z^(a) and Z^(b) are eachindependently selected from the group consisting of substituted orunsubstituted C₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl,—CO₂R^(50a), —OC(O)NR^(50a)R^(51a), —NR^(50a)C(O)NR^(51a)R^(51b),—NR^(50a)CO₂R^(51a), substituted or unsubstituted C₆₋₁₀ aryl andsubstituted or unsubstituted 3- to 10-membered heterocyclyl;

R^(50a), R^(51a) and R^(51b) are each independently selected from thegroup consisting of hydrogen, substituted or unsubstituted C₁₋₈ alkyl,substituted or unsubstituted 3- to 10-membered heterocyclyl, substitutedor unsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆alkynyl, substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl.

In one embodiment of formulae (I-C), Z^(a) and Z^(b) are eachindependently selected from the group consisting of substituted C₁₋₈alkyl, substituted C₂₋₈ alkenyl or substituted C₂₋₈ alkynyl, thesubstituted C₁₋₈ alkyl, substituted C₂₋₈ alkenyl or substituted C₂₋₈alkynyl may have 1 to 3 substituents each independently selected fromthe group consisting of halogen, oxo (═O or —O⁻), —OR⁵², —CO₂R⁵²,—C(O)R⁵², CONR⁵²R⁵³, —NR⁵²C(O)R⁵³, —NR⁵²R⁵³, —SR⁵², —S(O)R⁵², —S(O)₂R⁵²,—SO₂NR⁵²R⁵³, —NR⁵²SO₂R⁵³, unsubstituted or substituted phenyl,unsubstituted or substituted 5- to 6-membered heteroaryl, unsubstitutedor substituted 4- to 7-membered heterocyclyl, substituted orunsubstituted (C₁₋₄ alkyl)-(C₆₋₁₀ aryl), and substituted orunsubstituted (C₁₋₄ alkyl)-(5- to 10-membered heteroaryl);

R⁵² and R⁵³ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl.

In one embodiment of formulae (1-C), Z^(a) and Z^(b) are eachindependently selected from the group consisting of substituted phenyl,substituted 5- or 6-membered heteroaryl or substituted 4- to 7-memberedheterocyclyl, the substituted phenyl, substituted 5- or 6-memberedheteroaryl and substituted 4- to 7-membered heterocyclyl may have 1 to 3substituents independently selected from the group consisting ofhalogen, —OR⁵⁶, —CN, —NO₂, oxo (═O or —O⁻), —OC(O)R⁵⁶, —CO₂R⁵⁶,—C(O)R⁵⁶, —CONR⁵⁶R⁵⁷, —NR⁵⁶C(O)R⁵⁷, —NR⁵⁶R⁵⁷, —SR⁵⁶, —S(O)R⁵⁶,—S(O)₂R⁵⁶, —NR⁵⁶SO₂R⁵⁷, unsubstituted 4- to 7-membered heterocyclyl andunsubstituted C₁₋₈ alkyl, with the proviso that if the substituent onthe Z¹ group is heterocyclic, then the substituents on this heterocycledo not include another heterocycle;

R⁵⁶ and R⁵⁷ are each independently selected from the group consisting ofhydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted 3- to 10-membered heterocyclyl, substituted orunsubstituted C₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, and substituted orunsubstituted 5- to 10-membered heteroaryl.

In one embodiment of formulae (I-C), Z^(a) and Z^(b) are eachindependently selected from the group consisting of chlorine, fluorine,unsubstituted or substituted C₁₋₈ alkyl (particularly methyl andtrifluoromethyl), oxo (═O or —O⁻), —CN, —NO₂, —OMe, —C(O)Me, —CONH₂,—CONHMe, —CONMe₂, —NHC(O)Me, —NH₂, —NHMe, —NMe₂, —SMe, —S(O)Me,—S(O)₂Me, —NHSO₂Me, morpholinyl, —CH₂OH, —CH₂OMe, —CH₂NH₂, —CH₂NHMe, and—CH₂NMe₂.

In one embodiment of formulae (I-C), Z^(a) and Z^(b) are selected fromthe group consisting of chlorine, fluorine, methyl, oxo (═O or —O⁻),—CN, and —OMe.

In one embodiment of formulae (I-C), Z^(a) and Z^(b) are selected fromthe group consisting of chlorine, fluorine, methyl, isopropyl, oxo (═Oor —O⁻), —CN, and —OMe.

In one embodiment of formulae (I-C), one of Z^(a) and Z^(b) is hydrogenand one of Z^(a) and Z^(b) is selected from the group consisting ofchlorine, fluorine, methyl, isopropyl, oxo (═O or —O⁻), —CN, and —OMe.

In one embodiment of formulae (I-C), Z^(a) and Z^(b) are selected fromthe group consisting of chlorine, fluorine, methyl, isopropyl, oxo (═Oor —O⁻), —CN, —OMe, —S(O)Me, —SO₂Me, —CO₂H, and —CO₂Me.

In one embodiment of any of formulae (I-C) Z^(a) and Z^(b) are selectedfrom the group consisting of:

In a further embodiment, the compounds are represented by formula (CLI),or salts thereof:

Formula CLI is an example of Formula I.

X^(b), Y^(b) and Z^(b) are as defined above.

In one embodiment of formula (CLI), Y^(b) is halogen.

In one embodiment of formula (CLI), Y^(b) is Cl.

In one embodiment of formula (CLI), X^(b) is selected from the groupconsisting of —OR^(24a), and substituted or unsubstituted C₁₋₈ alkyl;and Z^(b) is selected from the group consisting of substituted orunsubstituted C₁₋₈ alkyl.

In a further embodiment, the compounds are represented by formula(CLII), or salts thereof:

Formula CLII is an example of Formula I.

X^(b) and Z^(b) are as defined above.

In one embodiment of formula (CLII), X^(b) is selected from the groupconsisting of —OR^(24a), and substituted or unsubstituted C₁₋₈ alkyl;and Z^(b) is —OR^(30a), where R^(30a) is selected from the groupconsisting of hydrogen and substituted or unsubstituted C₁₋₈ alkyl.

In a further embodiment, the compounds are represented by formula(CLIII), or salts thereof:

Formula CLIII is an example of Formula I.

X^(b) and Z^(b) are as defined above.

In one embodiment of formula (CLIII), X^(b) is selected from the groupconsisting of —OR^(24a), and substituted or unsubstituted C₁₋₈ alkyl;and Z^(b) is halogen. Preferably Z^(b) is fluorine.

In one embodiment of formulae (CLI-CLIII), X^(b) is —OR^(24a).

In one embodiment of formulae (CLI-CLIII), X^(b) is —OR^(24a); andR^(24a) is substituted or unsubstituted C₁₋₈ alkyl.

In one embodiment of formulae (CLI-CLIII), X^(b) is —OR^(24a); andR^(24a) is substituted C₁₋₈ alkyl.

In one embodiment of formulae (CLI-CLIII), X^(b) is isopropoxy.

In one embodiment of formulae (CLI-CLIII), X^(b) is substituted orunsubstituted C₁₋₈ alkyl.

In one embodiment of formulae (CLI-CLIII), X^(b) is substituted C₁₋₈alkyl or unsubstituted C₂₋₈ alkyl.

In one embodiment of formulae (CLI-CLIII), X^(b) is substituted C₁₋₈alkyl.

In one embodiment of formulae (CLI-CLIII), X^(b) is unsubstituted C₂₋₈alkyl.

In one embodiment of formulae (CLI-CLIII), X^(b) is tert-butyl.

In one embodiment of formulae (CLI), Z^(b) is unsubstituted C₁₋₈ alkyl.

In one embodiment of formulae (CLI), Z^(b) is methyl.

In one embodiment of formulae (CII), Z^(b) is —OR^(30a), where R^(30a)is unsubstituted C₁₋₈ alkyl.

In one embodiment of formulae (CLII), Z^(b) is —OR^(30a), where R^(30a)is substituted C₁₋₈ alkyl.

In one embodiment of formulae (CLII), Z^(b) is hydroxy.

In one embodiment of formulae (CLII), Z^(b) is methoxy.

In one embodiment of formulae (CLIII), Z^(b) is fluorine.

In one embodiment of formulae (CLIII), Z^(b) is chlorine.

In one embodiment of formulae (CLIII), Z^(b) is bromine.

In one embodiment of formulae (CLIII), Z^(b) is iodine.

Compositions that Modulate Chemokine Activity

In another aspect, the present invention provides compositions thatmodulate chemokine activity, specifically CCR2 activity or CCR9activity. Generally, the compositions for modulating chemokine receptoractivity in humans and animals will comprise a pharmaceuticallyacceptable excipient or diluent and a compound having the formulaprovided above as formula (I).

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self emulsifications as described in U.S. Pat. No.6,451,339, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions. Suchcompositions may contain one or more agents selected from sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with other non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents such as cellulose, silicon dioxide, aluminum oxide, calciumcarbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose,calcium phosphate or sodium phosphate; granulating and disintegratingagents, for example, corn starch, or alginic acid; binding agents, forexample PVP, cellulose, PEG, starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated enterically or otherwiseby known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in the U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such asmono-diglycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil in water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative. and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, axed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols. Additionally, the compounds can be administered via oculardelivery by means of solutions or ointments. Still further, transdermaldelivery of the subject compounds can be accomplished by means ofiontophoretic patches and the like.

For topical use, creams, ointments, jellies, solutions or suspensionscontaining the compounds of the present invention are employed. As usedherein, topical application is also meant to include the use of mouthwashes and gargles.

The pharmaceutical compositions and methods of the present invention mayfurther comprise other therapeutically active compounds as noted herein,such as those applied in the treatment of the above mentionedpathological conditions.

In one embodiment, the present invention provides a compositionconsisting of a pharmaceutically acceptable carrier and a compound ofthe invention.

Methods of Treatment

Depending on the disease to be treated and the subject's condition, thecompounds and compositions of the present invention may be administeredby oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous,ICV, intracisternal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topicalroutes of administration and may be formulated, alone or together, insuitable dosage unit formulations containing conventional non toxicpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each rouse of administration. The present invention alsocontemplates administration of the compounds and compositions of thepresent invention in a depot formulation.

In the treatment or prevention of conditions which require chemokinereceptor modulation an appropriate dosage level will generally be about0.001 to 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05to 0.5, 0.5 to 5.0, or 5.0 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, particularly1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, hereditary characteristics, generalhealth, sex, diet, mode and time of administration, rate of excretion,drug combination, the severity of the particular condition, and the hostundergoing therapy.

In still other embodiments, the present methods are directed to thetreatment of allergic diseases, wherein a compound or composition of theinvention is administered either alone or in combination with a secondtherapeutic agent, wherein said second therapeutic agent is anantihistamine. When used in combination, the practitioner can administera combination of the compound or composition of the present inventionand a second therapeutic agent. Also, the compound or composition andthe second therapeutic agent can be administered sequentially, in anyorder.

The compounds and compositions of the present invention can be combinedwith other compounds and compositions having related utilities toprevent and treat the condition or disease of interest, such asinflammatory conditions and diseases, including inflammatory boweldisease, allergic diseases, psoriasis, atopic dermatitis and asthma, andthose pathologies noted above. Selection of the appropriate agents foruse in combination therapies can be made one of ordinary skill in theart. The combination of therapeutic agents may act synergistically toeffect the treatment or prevention of the various disorders. Using thisapproach, one may be able to achieve therapeutic efficacy with lowerdosages of each agent, thus reducing the potential for adverse sideeffects.

In treating, preventing, ameliorating, controlling or reducing the riskof inflammation, the compounds of the present invention may be used inconjunction with an anti-inflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, such as an inhibitor of5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor,an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide, a non-steroidal anti-inflammatory agent, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, biological TNFsequestrants, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like.

Similarly, the compounds of the present invention may be administeredwith a pain reliever; a potentiator such as caffeine, an H2-antagonist,simethicone, aluminum or magnesium hydroxide; a decongestant such aspseudophedrine; an antitussive such as codeine; a diuretic; a sedatingor non-sedating antihistamine; a very late antigen (VLA-4) antagonist;an immunosuppressant such as cyclosporin, tacrolimus, rapamycin, EDGreceptor agonists, or other FK-506 type immunosuppressants; a steroid; anon-steroidal anti-asthmatic agent such as a β2-agonist, leukotrieneantagonist, or leukotriene biosynthesis inhibitor; an inhibitor ofphosphodiesterase type IV (PDE-IV); a cholesterol lowering agent such asa HMG-CoA reductase inhibitor, sequestrant, or cholesterol absorptioninhibitor; and an anti-diabetic agent such as insulin, α-glucosidaseinhibitors or glitazones.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith an NSAID the weight ratio of the compound of the present inventionto the NSAID will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of thepresent invention and other active ingredients will generally also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used.

Methods of Treating or Preventing CCR2-mediated Conditions or Diseases

In yet another aspect, the present invention provides methods oftreating or preventing a CCR2-mediated condition or disease byadministering to a subject having such a condition or disease atherapeutically effective amount of any compound of formula (I) above.Compounds for use in the present methods include those compoundsaccording to formula (I), those provided above as embodiments, thosespecifically exemplified in the Examples below, and those provided withspecific structures herein. The “subject” is defined herein to includeanimals such as mammals, including, but not limited to, primates (e.g.,humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice andthe like. In preferred embodiments, the subject is a human.

As used herein, the phrase “CCR2-mediated condition or disease” andrelated phrases and terms refer to a condition or disease characterizedby inappropriate, i.e., less than or greater than normal, CCR2functional activity. Inappropriate CCR2 functional activity might ariseas the result of CCR2 expression in cells which normally do not expressCCR2, increased CCR2 expression (leading to, e.g., inflammatory andimmunoregulatory disorders and diseases) or decreased CCR2 expression.Inappropriate CCR2 functional activity might also arise as the result ofMCP-1 secretion by cells which normally do not secrete MCP-1, increasedMCP-1 expression (leading to, e.g., inflammatory and immunoregulatorydisorders and diseases) or decreased MCP-1 expression. A CCR2-mediatedcondition or disease may be completely or partially mediated byinappropriate CCR2 functional activity. However, a CCR2-mediatedcondition or disease is one in which modulation of CCR2 results in someeffect on the underlying condition or disease (e.g., a CCR2 antagonistresults in some improvement in patient well being in at least somepatients). Furthermore, MCP-2, 3 and 4 are also CCR2 ligands.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease isatherosclerosis.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease is restenosis.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease is multiplesclerosis.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease is selected fromthe group consisting of inflammatory bowel disease, renal fibrosis,rheumatoid arthritis, obesity and non-insulin-dependent diabetes.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease is type 2diabetes.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the CCR2-mediated condition or disease is selected fromthe group consisting of chronic obstructive pulmonary disease,idiopathic pulmonary fibrosis and idiopathic pneumonia syndrome.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the administering is oral, parenteral, rectal,transdermal, sublingual, nasal or topical.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the compound is administered in combination with ananti-inflammatory or analgesic agent.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where an anti-inflammatory or analgesic agent is alsoadministered.

In one embodiment, the present invention provides a method of modulatingCCR2 function in a cell, where the CCR2 function in the cell ismodulated by contacting the cell with a CCR2 modulating amount of thecompound of the present invention.

In one embodiment, the present invention provides a method of treating aCCR2-mediated condition or disease involving administering to a subjecta safe and effective amount of the compound or composition of theinvention, where the disease is selected from the group consisting ofpulmonary fibrosis, transplantation rejection, graft-versus-host diseaseand cancer.

In yet other embodiments, the present methods are directed to thetreatment of psoriasis wherein a compound or composition of theinvention is used alone or in combination with a second therapeuticagent such as a corticosteroid, a lubricant, a keratolytic agent, avitamin D₃ derivative, PUVA and anthralin.

In other embodiments, the present methods are directed to the treatmentof atopic dermatitis using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as alubricant and a corticosteroid.

In further embodiments, the present methods are directed to thetreatment of asthma using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as a02-agonist and a corticosteroid.

Methods of Treating or Preventing CCR9-Mediated Conditions or Diseases

In yet another aspect, the present invention provides methods oftreating or preventing a CCR9-mediated condition or disease byadministering to a subject having such a condition or disease atherapeutically effective amount of any compound of formula (I) above.Compounds for use in the present methods include those compoundsaccording to formula (I), those provided above as embodiments, thosespecifically exemplified in the Examples below, and those provided withspecific structures herein. The “subject” is defined herein to includeanimals such as mammals, including, but not limited to, primates (e.g.,humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice andthe like. In preferred embodiments, the subject is a human.

As used herein, the phrase “CCR9-mediated condition or disease” andrelated phrases and terms refer to a condition or disease characterizedby inappropriate, i.e., less than or greater than normal, CCR9functional activity. Inappropriate CCR9 functional activity might ariseas the result of CCR9 expression in cells which normally do not expressCCR9, increased CCR9 expression (leading to, e.g., inflammatory andimmunoregulatory disorders and diseases) or decreased CCR9 expression.Inappropriate CCR9 functional activity might also arise as the result ofTECK secretion by cells which normally do not secrete TECK, increasedTECK expression (leading to, e.g., inflammatory and immunoregulatorydisorders and diseases) or decreased TECK expression. A CCR9-mediatedcondition or disease may be completely or partially mediated byinappropriate CCR9 functional activity. However, a CCR9-mediatedcondition or disease is one in which modulation of CCR9 results in someeffect on the underlying condition or disease (e.g., a CCR9 antagonistresults in some improvement in patient well being in at least somepatients).

The term “therapeutically effective amount” means the amount of thesubject compound that will elicit the biological or medical response ofa cell, tissue, system, or animal, such as a human, that is being soughtby the researcher, veterinarian, medical doctor or other treatmentprovider.

Diseases and conditions associated with inflammation, immune disorders,infection and cancer can be treated or prevented with the presentcompounds, compositions, and methods. In one group of embodiments,diseases or conditions, including chronic diseases, of humans or otherspecies can be treated with inhibitors of CCR9 function. These diseasesor conditions include: (1) allergic diseases such as systemicanaphylaxis or hypersensitivity responses, drug allergies, insect stingallergies and food allergies, (2) inflammatory bowel diseases, such asCrohn's disease, ulcerative colitis, ileitis and enteritis, (3)vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis,eczema, atopic dermatitis, allergic contact dermatitis, urticaria andpruritus, (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma,(8) asthma and respiratory allergic diseases such as allergic asthma,allergic rhinitis, hypersensitivity lung diseases and the like, (9)autoimmune diseases, such as fibromyalagia, scleroderma, ankylosingspondylitis, juvenile RA, Still's disease, polyarticular juvenile RA,pauciarticular juvenile RA, polymyalgia rheumatica, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, polyarticular arthritis,multiple sclerosis, systemic lupus erythematosus, type I diabetes, typeII diabetes, glomerulonephritis, and the like, (10) graft rejection(including allograft rejection), (11) graft-v-host disease (includingboth acute and chronic), (12) other diseases in which undesiredinflammatory responses are to be inhibited, such as atherosclerosis,myositis, neurodegenerative diseases (e.g., Alzheimer's disease),encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis,allergic conjunctivitis, otitis, chronic obstructive pulmonary disease,sinusitis, Behcet's syndrome and gout, (13) immune mediated foodallergies such as Coeliac (Celiac) disease (14) pulmonary fibrosis andother fibrotic diseases, and (15) irritable bowel syndrome.

In another group of embodiments, diseases or conditions can be treatedwith modulators and agonists of CCR9 function. Examples of diseases tobe treated by modulating CCR9 function include cancers, cardiovasculardiseases, diseases in which angiogenesis or neovascularization play arole (neoplastic diseases, retinopathy and macular degeneration),infectious diseases (viral infections, e.g., HIV infection, andbacterial infections) and immunosuppressive diseases such as organtransplant conditions and skin transplant conditions. The term “organtransplant conditions” is means to include bone marrow transplantconditions and solid organ (e.g., kidney, liver, lung, heart, pancreasor combination thereof) transplant conditions.

Preferably, the present methods are directed to the treatment ofdiseases or conditions selected from inflammatory bowel diseaseincluding Crohn's disease and Ulcerative Colitis, allergic diseases,psoriasis, atopic dermatitis and asthma, autoimmune disease such asrheumatoid arthritis and immune-mediated food allergies such as Celiacdisease.

In yet other embodiments, the present methods are directed to thetreatment of psoriasis where a compound or composition of the inventionis used alone or in combination with a second therapeutic agent such asa corticosteroid, a lubricant, a keratolytic agent, a vitamin D₃derivative, PUVA and anthralin.

In other embodiments, the present methods are directed to the treatmentof atopic dermatitis using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as alubricant and a corticosteroid.

In further embodiments, the present methods are directed to thetreatment of asthma using a compound or composition of the inventioneither alone or in combination with a second therapeutic agent such as a02-agonist and a corticosteroid.

Preparation of Modulators

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Additionally, those skilled in the art will recognize that the moleculesclaimed in this patent may be synthesized using a variety of standardorganic chemistry transformations.

Certain general reaction types employed widely to synthesize targetcompounds in this invention are summarized in the examples.Specifically, generic procedures for sulfonamide formation, pyridineN-oxide formation and 2-aminophenyl-arylmethanone synthesis viaFriedel-Crafts type approaches are given, but numerous other standardchemistries are described within and were employed routinely.

While not intended to be exhaustive, representative synthetic organictransformations which can be used to prepare compounds of the inventionare included below.

These representative transformations include; standard functional groupmanipulations; reductions such as nitro to amino; oxidations offunctional groups including alcohols and pyridines; aryl substitutionsvia IPSO or other mechanisms for the introduction of a variety of groupsincluding nitrile, methyl and halogen; protecting group introductionsand removals; Grignard formation and reaction with an electrophile;metal-mediated cross couplings including but not limited to Buckwald,Suzuki and Sonigashira reactions; halogenations and other electrophilicaromatic substitution reactions; diazonium salt formations and reactionsof these species; etherifications; cyclative condensations,dehydrations, oxidations and reductions leading to heteroaryl groups;aryl metallations and transmetallations and reaction of the ensuingaryl-metal species with an electrophile such as an acid chloride orWeinreb amide; amidations; esterifications; nucleophilic substitutionreactions; alkylations; acylations; sulfonamide formation;chlorosulfonylations; ester and related hydrolyses, and the like.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are within the scope of the invention.

In the descriptions of the syntheses that follow, some precursors wereobtained from commercial sources. These commercial sources includeAldrich Chemical Co., Acros Organics, Ryan Scientific Incorporated,Oakwood Products Incorporated, Lancaster Chemicals, Sigma Chemical Co.,Lancaster Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, andGFS Chemicals.

Compounds of the invention, including those listed in the table ofactivities, can be made by the methods and approaches described in thefollowing experimental section, and by the use of standard organicchemistry transformations that are well known to those skilled in theart.

Preparation of CCR2 and CCR9 Modulators

The following examples are offered to illustrate, but not to limit, theclaimed invention.

Additionally, those skilled in the art will recognize that the moleculesclaimed in this patent may be synthesized using a variety of standardorganic chemistry transformations.

Certain general reaction types employed widely to synthesize targetcompounds in this invention are summarized in the examples.Specifically, generic procedures for sulfonamide formation, pyridineN-oxide formation and 2-aminophenyl-arylmethanone synthesis viaFriedel-Crafts type approaches are given, but numerous other standardchemistries are described within and were employed routinely.

While not intended to be exhaustive, representative synthetic organictransformations which can be used to prepare compounds of the inventionare included below.

These representative transformations include; standard functional groupmanipulations; reductions such as nitro to amino; oxidations offunctional groups including alcohols and pyridines; aryl substitutionsvia IPSO or other mechanisms for the introduction of a variety of groupsincluding nitrile, methyl and halogen; protecting group introductionsand removals; Grignard formation and reaction with an electrophile;metal-mediated cross couplings including but not limited to Buckwald,Suzuki and Sonigashira reactions; halogenations and other electrophilicaromatic substitution reactions; diazonium salt formations and reactionsof these species; etherifications; cyclative condensations,dehydrations, oxidations and reductions leading to heteroaryl groups;aryl metallations and transmetallations and reaction of the ensuingaryl-metal species with an electrophile such as an acid chloride orWeinreb amide; amidations; esterifications; nuclephilic substitutionreactions; alkylations; acylations; sulfonamide formation;chlorosulfonylations; ester and related hydrolyses, and the like.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are within the scope of the invention.

In the descriptions of the syntheses that follow, some precursors wereobtained from commercial sources. These commercial sources includeAldrich Chemical Co., Acros Organics, Ryan Scientific Incorporated,Oakwood Products Incorporated, Lancaster Chemicals, Sigma Chemical Co.,Lancaster Chemical Co., TCI-America, Alfa Aesar, Davos Chemicals, andGFS Chemicals.

Compounds of the invention, including those listed in the table ofactivities, can be made by the methods and approaches described in thefollowing experimental section, and by the use of standard organicchemistry transformations that are well known to those skilled in theart.

EXAMPLES

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare tabulated in the order: multiplicity (br, broad; s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet) and number of protons.Mass spectrometry results are reported as the ratio of mass over charge,followed by the relative abundance of each ion (in parenthesis). Intables, a single m/e value is reported for the M+H (or, as noted, M−H)ion containing the most common atomic isotopes. Isotope patternscorrespond to the expected formula in all cases. Electrospray ionization(ESI) mass spectrometry analysis was conducted on a Hewlett-Packard MSDelectrospray mass spectrometer using the HP1100 HPLC for sampledelivery. Normally the analyte was dissolved in methanol at 0.1 mg/mLand 1 microliter was infused with the delivery solvent into the massspectrometer, which scanned from 100 to 1500 daltons. All compoundscould be analyzed in the positive ESI mode, using acetonitrile/waterwith 1% formic acid as the delivery solvent. The compounds providedbelow could also be analyzed in the negative ESI mode, using 2 mM NH₄OAcin acetonitrile/water as delivery system.

The following abbreviations have the following meanings:

-   -   BOP: (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium        hexafluorophosphate    -   DCM: dichloromethane    -   DIEA: diisopropylethyl amine    -   DMF: dimethylformamide    -   HATU: N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium        hexafluorophosphate    -   LAH: lithium aluminum hydride    -   NMP: N-methylpyrrolidinone    -   PMB: para methoxybenzyl    -   TEA: triethylamine    -   TFA: trifluoroacetic acid    -   T₃P: 1-propane phosphonic acid cyclic anhydride

This compound was prepared according to the following literatureprocedure: Zhou et al.; Bioorganic & Med. Chem., 9, 2061-2071 (2001).

Example 1: 2-Bromo-5-chloro-3-nitro-pyridine

This compound was prepared according to the following literatureprocedure: Zhou et al.; Bioorganic & Med. Chem., 9, 2061-2071 (2001).

Example 2: 2-Bromo-5-chloro-pyridin-3-ylamine

2-Bromo-5-chloro-3-nitro-pyridine (11.87 g, 50 mmol) was dissolved in100 mL ether. Tin(II) chloride dihydrate (56.4 g, 0.5 mol) was dissolvedin 100 mL of concentrated hydrochloric acid and added drop wise over 15minutes to the stirring ethereal solution of the nitro compound. Theexothermic reaction brought the ether to boiling and it was allowed toevaporate off. After the addition was complete the reaction mixture wasplaced on a 50° C. oil bath and stirred for 30 minutes to boil of theremaining ether. The flask was then cooled on in an ice bath. Theprecipitate formed was collected and by filtration and dissolved in 100mL of water. The pH was adjusted to 9-10 by the addition of concentratedammonium hydroxide solution and the product was extracted with ethylacetate (2×100 mL). The organic layer was washed with diluted ammoniumhydroxide, water and brine and dried over Na₂SO₄ and the solvent wasevaporated to afford 7.4 g of tan crystalline solid. MS m/z: 208.9(M+H).

Example 3: General Procedure A: Synthesis of5-chloro-3-nitro-2-aryloxy-pyridines and5-chloro-3-nitro-2-arylsulfanyl-pyridines

A mixture of the appropriate hydroxyaryl or thioaryl (1.3 equiv),2-bromo-5-chloro-3-nitro-pyridine (1 equiv) and K₂CO₃ (1.5 equiv) in DMFwas heated at 80° C. overnight. The resulting mixture was cooled to roomtemperature, and diluted with water and CH₂Cl₂. The biphasic mixture wasseparated and the aqueous portion was extracted with CH₂Cl₂. Thecombined extracts were washed with saturated aqueous NaHCO₃, brine anddried (Na₂SO₄). It was then filtered and filtrate was concentrated underreduced pressure and the product was purified by flash columnchromatography on silica gel to provide desired product.

Example 4: 5-Chloro-3-nitro-2-phenoxy-pyridine

This compound was prepared according to the general procedure Adescribed above using 2-bromo-5-chloro-3-nitro-pyridine (500 mg, 2.11mmol), phenol (258 mg, 2.75 mmol), K₂CO₃ (437 mg, 3.16 mmol) and DMF (2mL). MS m/z: 250.4 (M+H).

Example 5: 5-Chloro-3-nitro-2-(pyridin-4-ylsulfanyl)-pyridine

The title compound was prepared according to general procedure A using2-bromo-5-chloro-3-nitro-pyridine (500 mg, 2.11 mmol),4-mercaptopyridinel (306 mg, 2.75 mmol), K₂CO₃ (437 mg, 3.16 mmol) andDMF (2 mL). MS m/z: 267.5 (M+H).

Example 6: 5-Chloro-2-(2-fluoro-phenoxy)-3-nitro-pyridine

This compound was prepared according to general procedure A using2-bromo-5-chloro-3-nitro-pyridine (750 mg, 3.17 mmol), 2-fluorophenol(463 mmol, 4.13 mmol), K₂CO₃ (437 mg, 4.75 mmol) and DMF (5 mL). MS m/z:269.0 (M+H).

Example 7: 5-Chloro-2-(4-fluoro-phenoxy)-3-nitro-pyridine

The title compound was prepared according to general procedure A using2-bromo-5-chloro-3-nitro-pyridine (750 mg, 3.17 mmol), 4-fluorophenol(463 mmol, 4.13 mmol), K₂CO₃ (437 mg, 4.75 mmol) and DMF (5 mL). MS m/z:269.0 (M+H).

Example 8: 5-Chloro-3-nitro-pyridine-2-carboxylic Acid

Step 1

To a mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.6 mmol),CuI (141 mg, 0.74 mmol), Pd(PPh₃)₄, (367 mg, 0.32 mmol) and2-Methyl-3-butyn-2-ol (1.5 mL, 15.8 mmol) was added1-methyl-2-pyrrolidone (20 mL) followed by Et₃N (6 mL, 22 mmol). Afterstirring for 4 h 30 min at room temperature, the reaction mixture waspoured into water (20 mL) and extracted with EtOAc (3×30 mL). Thecombined organic extracts were washed with brine (20 mL), dried(Na₂SO₄), filtered and concentrated under reduced pressure, and theresidue was purified by flash column chromatography over silica gel(EtOAc/Hexanes, 2:98, then 5:95) to provide4-(5-chloro-3-nitro-pyridin-2-yl)-2-methyl-but-3-yn-2-ol. MS m/z: 241.0(M+H).

Step 2

A suspension of the alkyne from step 1 (1.96 g, 8.2 mmol) in water (20mL) was heated at 75-80° C. KMnO₄ (4.27 g, 27.1 mmol) was added portionwise over 30 min. After complete addition, heating was continued for 45min. The reaction mixture was then cooled to room temperature and the pHadjusted to 9 by the addition of 1.0M aqueous NaOH and filtered throughfilter paper. The filter cake was thoroughly washed with 0.3M aqueousNaOH. The filtrate was extracted with EtOAc and discarded. The aqueouspart was acidified to pH 3-4 with 1M HCl and saturated with solid NaCl.This solution was extracted with EtOAc (4×30 mL). The combined extractwas dried (Na₂SO₄) and concentrated under reduced pressure to providethe crude acid (500 mg). MS m/z: 200.8 (M−H).

Example 9: (5-Chloro-3-nitro-pyridin-2-yl)-phenyl-methanone

Step 1

To a stirred solution of the carboxylic acid (250 mg, 1.3 mmol) inCH₂Cl₂, at room temperature, was added oxalyl chloride (216 μL, 2.5mmol) followed by a drop of DMF. After stirring for 1-2 h, the reactionmixture the solvent was removed under reduced pressure to provide thechloride which was used in the next step without further purification.

Step 2

The above acid chloride was dissolved in benzene (30 mL) and AlCl₃ (246mg, 1.85 mmol) was added. The resulting mixture was heated at 80° C. for3.5 h. The reaction mixture was quenched with aqueous NaHCO₃. Theorganic phases then separated and the aqueous portion was extracted withEtOAc and the combined organic extracts washed with brine, dried(Na₂SO₄) and filtered. The filtrate was concentrated under reducedpressure and residue was purified by flash chromatography to on silicagel to provide the title compound. Mass spectrum m/z: 262.5 (M+H).

Example 10: (3-Amino-5-chloro-pyridin-2-yl)-phenyl-methanone

A mixture of (5-chloro-3-nitro-pyridin-2-yl)-phenyl-methanone (159 mg,0.61) and SnCl₂ (771 mg, 3.42 mmol) in EtOH (10 mL) was heated at 80° C.in an oil bath for several days. The progress of the reaction wasfollowed by LCMS and upon completion the solvent was removed and treatedwith aqueous NaOH to adjust the pH 10-11. This cloudy mixture wasextracted with EtOAc and washed with water and brine. The combinedextracts were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure and the residue was purified by flash columnchromatography to provide the aniline. Mass spectrum m/z: 232.6 (M+H).

Example 11: General Procedure B: Reduction of Nitropyridines

A mixture of the nitropyridine (1 equiv) and SnCl₂ (3-5 equiv) in EtOHwas heated at 80° C. in an oil bath for several hour. The progress ofthe reaction was followed by LCMS and upon completion the solvent wasremoved and treated with aqueous NaOH. This cloudy mixture was extractedwith EtOAc and washed with water and brine. The combined extracts weredried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure and the residue was purified by flash column chromatography toprovide the appropriate aminopyridine.

Example 12: 5-Chloro-2-phenoxy-pyridin-3-ylamine

This compound was prepared according to general procedure B using thecorresponding nitropyridine (500 mg, 2.11 mmol), SnCl₂ (1.77 mmol, 5.4mmol), and EtOH (10 mL). MS m/z: 220.5 (M+H).

Example 13: 5-Chloro-2-(2-fluoro-phenoxy)-pyridin-3-ylamine

The title compound was prepared according to general procedure B usingthe appropriate nitropyridine (450 mg, 1.67 mmol), SnCl₂ (1.50 mmol,6.68 mmol), and EtOH (10 mL). MS m/z: 239.0 (M+H).

Example 14: 5-Chloro-2-(4-fluoro-phenoxy)-pyridin-3-ylamine

The title compound was prepared according to general procedure B usingthe corresponding nitro compound (450 mg, 1.67 mmol), SnCl₂ (1.50 mmol,6.68 mmol) and EtOH (10 mL). Mass spectrum m/z: 239.0 (M+H).

Example 15: 5-Chloro-2-(pyridin-4-ylsulfanyl)-pyridin-3-ylamine

The title compound was prepared according to general procedure B usingthe corresponding nitro compound (296 mg, 1.11 mmol), SnCl₂ (1.00 gmmmol, 4.40 mmol), EtOH (10 mL) Reaction mixture was extracted with amixture of EtOAc and THF (1:1). MS m/z: 237.3 (M+H).

Example 16: (3-Amino-5-chloro-pyridin-2-yl)-pyridin-3-yl-methanone

Step 1

A mixture of pyridine-3-carboxaldehyde (0.5 mL) and5-Chloro-3-nitro-pyridine-2-carboxylic acid (200 mg) was heated at 190°C. for 4 minutes in a sealed tube using a microwave apparatus. Thereaction mixture was diluted with CH₂Cl₂ and concentrated under reducedpressure. This residue was washed with aqueous NaHCO₃ and extracted withEtOAc. The combined organic extracts washed with brine, dried (Na₂SO₄)and filtered. The residue which contained the desired alcohol wasutilized in the following oxidation without further purification. MSm/z: 266.0 (M+H).

Step 2

A mixture of the alcohol obtained from the above reaction and PCC (426mg) was stirred at room temperature for 2 h. It was then treated withsmall amount of silica gel and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified by flash columnchromatography on silica gel to provide the ketone. MS m/z: 264.0 (M+H).

Step 3

A mixture of the (5-Chloro-3-nitro-pyridin-2-yl)-pyridin-3-yl-methanonefrom Step 2 above (30 mg, 0.11 mmol) and SnCl₂ (200 mg, 0.88 mmol) inEtOH (3 mL) was heated at 80° C. in an oil bath for 3 days. The progressof the reaction was followed by LCMS and upon completion the solvent wasremoved and treated with aqueous NaOH to adjust the pH to 10-11. Thiscloudy mixture was extracted with EtOAc and washed with water and brine.The combined extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure and the residue separated bypreparative HPLC (20→80% gradient of ACN-water) and pure productfractions were treated with NaHCO₃ and extracted with EtOAc to provide(3-amino-5-chloro-pyridin-2-yl)-pyridin-3-yl-methanone. MS m/z: 234.1(M+H).

Example 17:4-Chloro-N-(5-chloro-2-phenoxy-phenyl)-3-trifluoromethyl-benzenesulfonamide

To a solution of 5-chloro-2-phenoxy-phenylamine (75 mg, 0.34 mmol) inanhydrous pyridine (0.5 mL) was added drop wise a solution of4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (95 mg, 0.341 mmol)in pyridine (0.5 mL). The resulting mixture was stirred at roomtemperature for 2 h. The reaction mixture was separated by preparativeHPLC using acetonitrile-water solvent mixture and pure product fractionswere lyophilized to provide pure product as a solid. ¹H NMR (400 MHz,CDCl₃) δ 8.04 (d, J=2.0 Hz, 1H), 7.80 (dd, J=8.4, 2.0 Hz, 1H), 7.70 (d,J=2.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.27-7.23 (m, 2H), 7.14-7.10 (m,1H), 7.05-7.02 (m, 2H), 6.66 (d, J=8.4 Hz, 1H), 6.60-6.56 (m, 2H). MSm/z: 484.0 (M+Na).

Example 18:4-Chloro-N-(5-chloro-2-phenoxy-pyridin-3-yl)-3-trifluoromethyl-benzeneSulfonamide

To a solution of 5-chloro-2-phenoxy-pyridin-3-ylamine (60 mg, 0.27 mmol)in anhydrous pyridine (0.5 mL) was added drop wise a solution of4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (76 mg, 0.27 mmol)in pyridine (0.5 mL). The resulting mixture was stirred at roomtemperature for 5 h. The reaction mixture was separated by preparativeHPLC using acetonitrile-water solvent mixture and pure product fractionswere lyophilized to provide pure product as a solid. ¹H NMR (400 MHz,CDCl₃) δ 8.14 (s, 1H), 7.89-7.87 (m, 2H), 7.81 (m, 1H), 7.59 (d, J=8.0Hz, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.25-7.19 (m, 2H), 6.76 (d, J=8.0 Hz,2H). MS m/z: 463.0 (M+H).

Example 19:4-Chloro-N-[5-chloro-2-(pyridin-4-ylsulfanyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

To a solution of 5-chloro-2-(pyridin-4-ylsulfanyl)-pyridin-3-ylamine(100 mg, 0.42 mmol) in anhydrous pyridine (0.5 mL) was added drop wise asolution of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (117 mg,0.42 mmol) in pyridine (0.25 mL). The resulting mixture was stirred atroom temperature for 2 days. The reaction mixture was concentrated underreduced pressure and diluted with EtOAc and brine. The aqueous portionwas separated and extracted with EtOAc. The combined extracts were dried(Na₂SO₄) filtered and concentrated under reduced pressure. The residuewas treated with 0.3M aqueous NaOH and washed with CH₂Cl₂. The aqueousportion was acidified with conc HCl to pH 3 and extracted with EtOAc.The combined extracts were dried (Na₂SO₄) filtered and concentratedunder reduced pressure. The residue was separated by preparative HPLC(20→80% gradient of ACN-water) and pure product fractions werelyophilized to provide pure product as a solid. Mass spectrum m/z: 480.0(M+H).

Example 20:4-Chloro-N-[5-chloro-2-(2-fluoro-phenoxy)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A solution of 5-chloro-2-(2-fluoro-phenoxy)-pyridin-3-ylamine (75 mg,0.31 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (103 mg,0.36 mmol), DMAP (20 mg, 0.16 mmol) in anhydrous pyridine (1 mL) wasstirred at room temperature for 2 days. The reaction product wasseparated by preparative HPLC using acetonitrile-water solvent mixtureand pure product fractions were lyophilized to provide pure product as asolid. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.96 (s, 1H), 7.89 (d,J=8.0 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.15-7.13 (m, 3H),7.00-6.96 (m, 1H). MS m/z: 481.0 (M+H).

Example 21:4-Chloro-N-[5-chloro-2-(2-fluoro-phenoxy)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A solution of 5-chloro-2-(4-fluoro-phenoxy)-pyridin-3-ylamine (75 mg,0.31 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (103 mg,0.36 mmol), DMAP (20 mg, 0.16 mmol) in anhydrous pyridine (1 mL) wasstirred at room temperature for 2 days. The reaction mixture wasseparated by preparative HPLC and pure product fractions werelyophilized to provide pure product as a solid. ¹H NMR (400 MHz, CDCl₃)δ □8.16 (s, 1H), 7.92-7.90 (m, 2H), 7.81 (s, 1H), 7.64 (d, J=7.6 Hz,1H), 7.11 (s, 1H), 7.06-7.03 (m, 2H), 6.76-6.74 (m, 2H). Mass spectrumm/z: 481.0 (M+H).

Example 22:N-(2-Benzoyl-5-chloro-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzeneSulfonamide

A solution of (3-amino-5-chloro-pyridin-2-yl)-phenyl-methanone (40 mg,0.17 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (72 mg,0.26 mmol), and DMAP (11 mg, 0.09 mmol) in anhydrous pyridine (0.5 mL)was heated at 60° C. for 4 days. The product was separated bypreparative HPLC and pure product fractions were lyophilized to providepure product as a solid. ¹H NMR (400 MHz, CDCl₃) δ□10.56 (s, 1H), 8.39(s, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.54 (d,J=7.6 Hz, 2H), 7.61-7.58 (m, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.45-7.42 (m,2H); MS m/z: 475.0 (M+H).

Example 23:4-Chloro-N-[5-chloro-2-(pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A solution of (3-amino-5-chloro-pyridin-2-yl)-pyridin-3-yl-methanone (26mg, 0.11 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (28mg, 0.10 mmol), DMAP (7.3 mg, 0.06 mmol) in anhydrous pyridine (0.5 mL)was heated at 60° C. for 2 days. The reaction mixture was separated bypreparative HPLC and pure product fractions were lyophilized to providepure product as a solid. ¹H NMR (400 MHz, CDCl₃) δ 11.03 (s, 1H), 9.15(s, 1H), 8.81-8.80 (m, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.29-8.26 (m, 1H),8.20-8.18 (m, 2H), 7.98 (dd, J=8.4, 2.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H),7.51-7.48 (m, 1H). Mass spectrum m/z: 476.0 (M+H).

Example 24:N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide

A mixture of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (1.5 g,5.3 mmol) and 2-bromo-5-chloro-pyridin-3-ylamine (500 mg, 2.4 mmol)dissolved in pyridine (20 mL) was heated at 60° C. for 16 h. The solventwas evaporated and the residue suspended in a 1:1 mixture of 2M NaOH andmethanol (20 mL) and heated at 70° C. for 30 min. The methanol wasevaporated under reduced pressure and the residue diluted with 15 mLwater. The solution was cooled on ice bath and the pH was adjusted to 3by drop wise addition of concentrated HCl. The solid formed wascollected by filtration and the product was purified by flashchromatography on silica gel column to afford the desired product. MSm/z: 450.8 (M+H).

Example 25:N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide(100 mg, 0.22 mmol) and K₂CO₃ (91 mg, 0.66 mmol) in THF (5 mL) was addedchloromethyl methyl ether (0.054 mL, 0.66 mmol) at room temperature. Theresulting mixture was stirred for 3 h at room temperature then filtered.The filter cake was washed with THF and the combined filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography to provide desired product. Mass spectrumm/z: 494.9 (M+H).

Example 26:4-Chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solutionN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(105 mg, 0.21 mmol) in anhydrous THF (3 mL) was added 2Misopropylmagnesiumbromide (0.15 mL, 0.3 mmol) at −60° C. The solutionwas then slowly warmed to room temperature over 1 h and stirred at roomtemperature for 20 minutes. At this point the reaction mixture turnsbrownish and additional 0.05 mL of isopropylmagnesiumbromide solutionwas added and stirring continued for 10 minutes. It was then cooled to−40° C. and pyridine-4-carboxaldehyde (0.05 mL, 0.52 mmol) was added.After 1.5 h the reaction mixture was quenched with brine and extractedwith Et₂O. The combined extract was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel to provide alcohol. Mass spectrumm/z: 522.0 (M+H).

Example 27:4-Chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

4-Chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(30 mg, 0.06 mmol) in 50% aqueous of MeOH (10 mL) was treated with 5-10drops of conc. HCl and heated at 80° C. for 3 days. The resultingmixture was cooled to room temperature, concentrated under reducedpressure and neutralized with aqueous NaHCO₃ to pH 7. It was thenextracted with EtOAc to provide crude4-chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamidewhich was purified by preparative HPLC. ¹H NMR (400 MHz, CDCl₃) δ 8.34(br, 2H), 8.29 (d, J=2.0 Hz, 1H), 7.97 (s, 1H), 7.91 (s, 1H), 7.44 (d,J=8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.11 (d, J=5.6 Hz, 2H), 5.98 (s,1H); MS m/z: 478.0 (M+H).

Example 28:4-Chloro-N-[5-chloro-2-(pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(15 mg, 0.03 mmol) and PCC (15 mg) was stirred at room temperature for 2h. It was then treated with small amount of silica gel and filtered. Thefiltrate was concentrated under reduced pressure to provide the crudeketone. ¹H NMR (400 MHz, CDCl₃) δ 10.90 (br s, 1H), 8.78 (dd, J=4.4, 1.6Hz, 2H), 8.35 (d, J=2.0 Hz, 1H), 8.19-8.17 (m, 2H), 7.98 (dd, J=8.4, 2.0Hz, 1H), 7.65-7.61 (m, 3H). MS m/z: 476.0 (M+H).

Example 29:4-Chloro-N-[5-chloro-2-(6-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Step 1

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(90 mg, 0.2 mmol) in 2.0 mL of THF under nitrogen atmosphere at −78° C.was added drop-wise 0.3 mL (0.6 mmol) of isopropylmagnesium chloride.The mixture was then stirred for 10 min at −78° C. followed by warmingto room temperature and stirred at that temperature for 30 min. Themixture was cooled to 0° C. (ice water) and a solution ofN-methoxy-6,N-dimethyl-nicotinamide (72 mg, 0.4 mmol) in 1 mL of THF wasadded. The mixture was stirred at room temperature for 3 hours, quenchedwith 1M HCl and neutralized with 1M NaOH until pH was 9. The mixture wasextracted with ethyl acetate, dried and concentrated. The residue waspurified by flash column (silica gel, 50% ethyl acetate in hexane) toafford 36 mg of4-chloro-N-[5-chloro-2-(6-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideasan off white solid. MS: (M+H)/z=534.0.

Step 2

A mixture of4-Chloro-N-[5-chloro-2-(6-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(30 mg) in 3 mL of 4M HCl in dioxane and 1 mL of water was refluxed for3 hours. After cooling to rt the mixture was diluted with water andsodium bicarbonate was added until pH was 9. The mixture was extractedwith ethyl acetate, dried and concentrated. The residue was furtherpurified via flash column (70% ethyl acetate in hexane) to afford 9.1 mgof title compound as an off white solid. ¹H NMR: (400 MHZ, CDCl₃) δ 8.97(m, 1H), 8.35 (m, 1H), 8.16-8.13 (m, 2H), 8.08-8.05 (m, 1H), 7.93-7.91(m, 1H), 7.59-7.57 (m, 1H), 7.25-7.23 (1H), 2.63 (s, 3H). MS:(M+H)/z=490.0.

Example 30:4-Chloro-N-[5-chloro-2-(2-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared by procedure analogous to that describedin Example 29 usingN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideand N-methoxy-2,N-dimethyl-nicotinamide. ¹H NMR: (400 MHZ, CDCl₃) δ 8.61(m, 1H), 8.26 (m, 1H), 8.20 (m, 1H), 8.17 (m, 1H), 8.04-8.01 (m, 1H),7.67 (d, 1H), 7.50 (m, 1H), 7.18 (m, 1H), 2.41 (s, 3H). MS:(M+H)/z=490.0.

Example 31:4-Chloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Step 1

A solution of lithium aluminum hydride in THF (1.0M, 40 mL, 40 mmol)placed in a 100-mL round bottom flask equipped with a magnetic stirringbar was cooled in an ice bath and cautiously treated with a solution of2,4-dimethyl-nicotinic acid ethyl ester (5.4 g, 30 mmol) in anhydrousTHF (10 mL) over 5 min period. After the addition was complete the coldbath was removed and the mixture was allowed to stir at room temperaturefor 2 h. The reaction mixture was then cooled in an ice bath and theexcess LAH was quenched by drop wise addition of water until gasevolution stopped. The reaction mixture was then basified with 2M NaOHto pH 9-10. Ether (100 mL) was added the mixture was washed with 1MNaOH, water and brine. The organic layer was dried over MgSO₄ and thesolvent was evaporated to yield (2,4-dimethyl-pyridin-3-yl)-methanol asa white solid. MS: (M+H)/z=138.

Step 2

A magnetically stirred mixture of (2,4-dimethyl-pyridin-3-yl)-methanol(0.342 g, 2.5 mmol) and IBX (1.40 g, 5 mmol) in acetonitrile (5 mL)placed in a round bottom flask was heated at 80° C. in an oil bath for 1h. The mixture was cooled to room temperature and filtered. The solidwas washed with acetonitrile. The filtrate was concentrated and appliedto a short silica gel column and chromatographed using hexane/ethylacetate solvent mixture (30-60% ethyl acetate). Product containingfractions were combined and the solvent was evaporated to afford 0.283 gof 2,4-dimethyl-pyridine-3-carbaldehyde as a white solid. MS:(M+H)/z=136.

Step 3

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(0.494 g, 1 mmol) placed in a 10 mL round bottom flask under nitrogenatmosphere was dissolved in anhydrous THF (5 mL). The solution wascooled to −20° C. The magnetically stirring solution was treated withsolution of 2.0M isopropylmagnesium bromide in THF (1.05 mL, 2.1 mmol)drop wise and after the addition was complete the reaction mixture wasallowed to warm to 0° C. and maintained at this temperature for 1 h. Theresulting deep purple solution was cooled to −20° C. and treated with asolution of 2,4-dimethyl-pyridine-3-carbaldehyde (0.28 g, 2.1 mmol) inTHF (2 mL). The mixture was allowed to warm to room temperature andstirred at room temperature over night. After diluting with saturatedammonium chloride solution (10 mL) the product was extracted with ethylacetate (3×25 mL). The combined organic extract was concentrated andproduct purified by flash chromatography on silica gel column (10-30%ethyl acetate in hexanes). Product containing fractions were combinedand the solvent evaporated to afford 0.33 g of4-chloro-N-{5-chloro-2-[(2,4-dimethyl-pyridin-3-yl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideas an off white solid. MS: (M+H)/z=550.

Step 4

The product obtained from Step 3 above was oxidized with IBX accordingto the procedure described in Step 2 and the product was purified byflash chromatography on silica gel column (30-50% ethyl acetate inhexanes) to afford4-chloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideas a light yellow solid. MS: (M+H)/z=548.

Step 5

The product from Step 4 above (60 mg, 0.1 mmol) was dissolved in 4M HClin dioxane (4 mL). Water (1 mL) was added and the mixture was refluxedfor 2 h. The solvent was evaporated and the residue was dissolved 20%aqueous acetonitrile and lyophylization yielded4-chloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamideas the hydrochloride salt. ¹H NMR: (400 MHZ, DMSO-d₆) δ 8.55 (d, J=6 Hz,1H), 8.45 (d, J=2 Hz, 1H), 8.32 (d, J=2 Hz, 1H), 8.18-8.15 (m, 1H), 8.05(d, J=2 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.53 (m, 1H), 2.20 (s, 3H),2.03 (s, 3H). MS: (M+H)/z=504.

Example 32: 2-Methyl-pyridine-4-carbaldehyde

(2-Methyl-pyridin-4-yl)-methanol (1.3 g, 10.6 mmol) (prepared accordingto the literature procedure, see Ragan, J. A. et al. Synthesis, 2002, 4,483-486) and MnO₂ (5.0 g, 57.5 mmol) in CHCl₃ (50 mL) was refluxed for18 h. The reaction mixture was cooled to room temperature and filtered.The filter cake was washed with CHCl₃ (2×100 mL). The combined filtrateswere concentrated under reduced pressure and the resulting residue waspurified by flash column chromatography on silica gel (EtOAc/Hexanes,3:7) to provide desired aldehyde. Mass spectrum m/z: 122.1 (M+H).

Example 33: (2-Methyl-1-oxy-pyridin-4-yl)-methanol

A mixture of (2-methyl-pyridin-4-yl)-methanol (1.1 g, 8.9 mmol) andm-CPBA (2.5 g, 10.7 mmol, 75% pure) in CH₂Cl₂ (50 mL) was stirred atroom temperature for 18 h. The reaction mixture was concentrated to 10mL under reduced pressure and the resulting residue was purified byflash column chromatography on silica gel (MeOH/CH₂Cl₂, 1:99, then 1:19,then, 2:23) to provide desired the title compound. Mass spectrum m/z:140.1 (M+H).

Example 34: 2-Methyl-1-oxy-pyridine-4-carbaldehyde

A mixture of alcohol (1.3 g, 5.04 mmol) and MnO₂ (3.0 g, 34.5 mmol) inCHCl₃ (50 mL) was refluxed for 18 h. The reaction mixture was cooled toroom temperature and filtered. The filter cake was washed with CHCl₃(2×100 mL). The combined filtrates were concentrated under reducedpressure to provide desired aldehyde. Mass spectrum m/z: 138.0 (M+H).

Example 35:4-Chloro-N-{5-chloro-2-[hydroxy-(2-methyl-1-oxy-pyridin-4-yl)-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(494 mg, 1.0 mmol) in anhydrous THF (10 mL) was added 2Misopropylmagnesiumchloride in THF (1.20 mL, 2.4 mmol) at −40° C. After 5minutes dry ice-acetone bath was replaced with a ice water bath andstirred at 0° C. for 1 h. Solid 2-methyl-1-oxy-pyridine-4-carbaldehyde(382 mg, 2.7 mmol) was added in one portion and the progress of thereaction was followed by LCMS. The reaction mixture was warmed to roomtemperature and stirred for 6 h and stirred overnight. It was thenquenched with saturated aqueous NH₄Cl (2 mL), and extracted with EtOAc.The combined extracts were dried (Na₂SO₄), filtered and concentratedunder reduced pressure to provide the desired product which was utilizedin the following step without further purification. MS m/z: 552.0 (M+H).

Example 36:4-Chloro-N-[5-chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution of the alcohol from Example 35 (˜500 mg) inanhydrous CHCl₃ (50 mL) was added MnO₂ (2.00 g, 23 mmol). The resultingmixture was heated at reflux for 2 days. The reaction mixture was cooledto room temperature and filtered through a filter paper and the filtercake was washed with EtOAc. The filtrate was partitioned between EtOAcand brine. The organic portion was separated and aqueous part wasextracted with EtOAc. The combined extracts were dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel to provide thedesired ketone (EtOAc/Hexanes, 2:3 then MeOH/CH₂Cl₂, 3:97). Massspectrum m/z: 550.0 (M+H).

Example 37:4-Chloro-N-[5-chloro-2-(2-methyl-1-oxy-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of mom-protected sulfonamide (150 mg, 0.27 mmol) in 4M HCl indioxane (10 mL), and water (4 mL) was heated at 100° C. for 3 h. Thereaction mixture was concentrated to dryness under reduced pressure andit was treated with aqueous NaHCO₃ to adjust pH to 5-6 and extractedwith EtOAc. The combined extracts were dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (MeOH: CH₂Cl₂: 1:99, then 2:98) toprovide the desired product. ¹H NMR (400 MHz, CDCl₃) δ 10.86 (s, 1H),8.39 (s, 1H), 8.24 (d, J=6.8 Hz, 1H), 8.18-8.14 (m, 2H), 7.95 (d, J=9.2Hz, 1H), 7.90 (s, 1H), 7.82 (d, J=6.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H),2.54 (s, 3H); MS m/z: 506.0 (M+H).

Example 38:4-Chloro-N-{5-chloro-2-[hydroxy-(2-methyl-pyridin-4-yl)-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethylBenzenesulfonamide

To a stirred solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(494 mg, 1.0 mmol) in anhydrous THF (10 mL) was added 2Misopropylmagnesiumchloride in THF (1.20 mL, 2.4 mmol) at −40° C. After 5minutes dry ice-acetone bath was replaced with a ice water bath andstirred at 0° C. for 1 h. Solid 2-methyl-pyridine-4-carbaldehyde (327mg, 2.7 mmol) was added in one portion and the progress of the reactionwas followed by LCMS. The reaction mixture was warmed to roomtemperature and stirred overnight. It was then quenched with saturatedaqueous NH₄Cl (2 mL), and extracted with EtOAc. The combined extractswere dried (Na₂SO₄), filtered and concentrated under reduced pressure toprovide the desired product which was utilized in the following stepwithout further purification. MS m/z: 536.0 (M+H).

Example 39:4-Chloro-N-[5-chloro-2-(2-methyl-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution of4-chloro-N-[5-chloro-2-(2-methyl-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(˜500 mg) in anhydrous CHCl₃ (50 mL) was added MnO₂ (2.00 g, 23 mmol).The resulting mixture was heated at reflux for 4 days. The reactionmixture was cooled to room temperature and filtered through a filterpaper and the filter cake was washed with EtOAc. The filtrate waspartitioned between EtOAc and brine. The organic portion was separatedand aqueous part was extracted with EtOAc. The combined extracts weredried (Na₂SO₄), filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel toprovide the desired ketone (EtOAc/Hexanes, 2:3 then 4:1). MS m/z: 534.0(M+H).

Example 40:4-Chloro-N-[5-chloro-2-(2-methyl-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-Chloro-N-[5-chloro-2-(2-methyl-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(150 mg, 0.27 mmol) from Example 39 dissolved in 4M HCl in dioxane (10mL), and water (4 mL) was heated at 100° C. for 3 h. The reactionmixture was concentrated to dryness under reduced pressure and it wastreated with aqueous NaHCO₃ to adjust pH to 5-6 and extracted withEtOAc. The combined extracts were dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel (MeOH: CH₂Cl₂: 1:99, then 2:98) toprovide the desired product. ¹H NMR (400 MHz, CDCl₃) δ 10.9 (s, 1H),8.64 (d, J=5.2 Hz, 1H), 8.36 (s, 1H), 8.18-8.16 (m, 2H), 7.96 (d, J=8.4Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.41-7.38 (m, 2H), 2.64 (s, 3H); MSm/z: 490.0 (M+H).

Example 41:4-Chloro-N-[5-chloro-2-(4-chloro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared by procedure analogous to that describedin Example 29 usingN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideand 4-chloro-N-methoxy-N-methyl-benzamide ¹H NMR (400 MHz, CDCl₃)δ□10.61 (s, 1H), 8.37 (m, 1H), 8.16 (m, 1H), 8.09 (m, 1H), 7.84 (m, 1H),7.77-7.75 (m, 2H), 7.53 (m, 1H), 7.42-7.40 (m, 2H), 7.23 (m, 1H) MS:(M+H)/z=509.0.

Example 42:4-Chloro-N-[3-(morpholine-4-carbonyl)-pyrazin-2-yl]-3-trifluoromethyl-benzenesulfonamide

Step 1

To a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester (153mg, 1.0 mmol) in 2.0 mL of pyridine was added4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (279 mg, 1.0 mmol)in 1.0 mL of pyridine. The mixture was stirred at room temperature for16 h, diluted with 15 mL of ethyl acetate, washed twice with 1M HCl (15mL), dried on MgSO₄ and the solvent was evaporated. The product waspurified on silica gel column (15% ethyl acetate in hexane) to afford185 mg of3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyrazine-2-carboxylicacid methyl ester as white powder. MS: (M+H)/z=396.0.

Step 2

A mixture of3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyrazine-2-carboxylicacid methyl ester (60 mg), 3 mL of 2N NaOH and 3 mL of methanol wasstirred at room temperature overnight. To the reaction mixture was addedslowly 2M HCl until white solid precipitated. Filtration followed byvacuum drying afforded3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyrazine-2-carboxylicacid as a white solid. MS: (M+H)/z=382.0.

Step 3

To a mixture of 20 mg of3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyrazine-2-carboxylicacid, 10 mg of morpholine and 20 μl of DIEA in 1.5 mL of CH₂Cl₂ wasadded 32 μL of 1-propanephosphonic acid cyclic anhydride (50% in ethylacetate). After 3-4 hours the reaction mixture was directly purified viaflash column (65% ethyl acetate in hexane) to afford 14 mg of4-chloro-N-[3-(morpholine-4-carbonyl)-pyrazin-2-yl]-3-trifluoromethyl-benzenesulfonamideas a white powder. MS: (M+H)/z=451.0.

Example 43: 3-(3,4-Dichloro-benzenesulfonylamino)-pyrazine-2-carboxylicAcid

This title compound was prepared following procedure described inexample 42 step 2 wherein3-(3,4-dichloro-benzenesulfonylamino)-pyrazine-2-carboxylic acid methylester was treated with 2M NaOH and methanol. Usual work up afforded theabove title product as a white powder. MS: (M+Na)/z=382.0.

Example 44:3,4-Dichloro-N-[3-(morpholine-4-carbonyl)-pyrazin-2-yl]benzenesulfonamide

This title compound was prepared following procedure described inexample 42 step 3 wherein3-(3,4-dichloro-benzenesulfonylamino)-pyrazine-2-carboxylic acid wascoupled with morpholine. The crude was purified by flash column (65%ethyl acetate in hexane) to afford the above title product as a whitepowder. MS: (M+Na)/z=451.0.

Example 45:N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide

A 200 mL round-bottom flask was charged with2-bromo-5-chloro-pyridin-3-ylamine (10.4 g, 50.0 mmol),4-tert-butyl-benzenesulfonyl chloride (20.0 g, 85.0 mmol), and pyridine(38 mL). The resultant solution was heated to 70° C. and stirredovernight. The following day, the pyridine was removed in vacuo and THF(30 mL) and 4.0N NaOH (100 mL) were added and the reaction was stirredat 60° C. overnight. The organics were subsequently removed in vacuo andthe residues were diluted with water (400 mL). The small quantity ofinsoluble solid was removed by filtration and the pH was adjusted to 6-7with concentrated HCl. The resultant aqueous solution was extracted withEtOAc, washed with brine, dried over MgSO₄, and concentrated underreduced pressure to afford the diarylsulfonamide (13.4 g) in 66% yield.To a solution of the crude sulfonamide (12.0 g, 35.0 mmol) and K₂CO₃(24.0 g, 170 mmol) in anhydrous THF (80 mL) was added chloromethylmethyl ether (4.0 mL, 52.7 mmol). The resultant heterogeneous solutionwas stirred for 60 min at ambient temperature and the solids weresubsequently removed via filtration. The filtrate was then removed invacuo and the residue was dissolved in EtOAc. The organics were washedwith saturated Na₂CO₃, dried over MgSO₄, and evaporated in vacuo togenerate a brownish oil. The oil was triturated with hexanes and theresultant solid filtered to produce the desired product as a lightyellowish solid (11.5 g, 86% yield).

Example 46:4-tert-Butyl-N-[5-chloro-2-(2-methyl-pyridin-3-yloxy)-pyridin-3-yl]-benzenesulfonamide

A 5 mL pear-shaped flask was charged withN-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(134 mg, 0.30 mmol), 4-methyl-pyridin-3-ol (100 mg, 0.90 mmol),potassium carbonate (250 mg, 18.0 mmol), and DMA (0.9 mL). Theheterogeneous mixture was heated to 150° C. and stirred overnight. Thecrude reaction mixture was subsequently purified via reverse phase HPLC(Column: Varian Dynamax 250×21.4 mm Microsorb100-8 C18, 0.1% TFA/H₂O(Eluent A): 0.1% TFA/MeCN (Eluent B)): ¹H NMR (400 MHz, CDCl₃) δ 8.06(d, 1H), 7.95 (d, 1H), 7.76 (d, 2H), 7.73 (d, 1H), 7.50 (d, 2H), 7.12(d, 1H), 7.04 (dd, 1H), 2.55 (s, 3H), 1.34 (s, 9H); MS (ES) M+H expect432.1, found 432.5.

Example 47:4-tert-Butyl-N-(5-chloro-2-phenoxy-pyridin-3-yl)-benzenesulfonamide

A 5 mL pear-shaped flask was charged withN-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(134 mg, 0.30 mmol), phenol (85 mg, 0.90 mmol), potassium carbonate (250mg, 18.0 mmol), and DMA (0.9 mL). The heterogeneous solution was heatedto 150° C. and stirred overnight. The crude reaction mixture wassubsequently purified via reverse phase HPLC (Column: Varian Dynamax250×21.4 mm Microsorb100-8 C18, 0.1% TFA/H₂O (Eluent A): 0.1% TFA/MeCN(Eluent B)): ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, 1H), 7.75 (d, 1H), 7.72(d, 2H), 7.48 (d, 2H), 7.28-7.34 (m, 2H), 7.17-7.21 (m, 1H), 7.05 (bs,1H), 6.71-6.76 (m, 2H), 1.34 (s, 9H); MS (ES) M+H expect 417.1, found417.4.

Example 48:4-tert-Butyl-N-[5-chloro-2-(2-fluoro-benzoyl)-pyridin-3-yl]-benzenesulfonamide

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask.The flask was evacuated and purged with nitrogen, followed by theaddition of THF (1 mL). The homogeneous mixture was lowered to −5° C.and iPrMgCl (0.33 mL, 2.0M) was added dropwise. Upon completion of theaddition, the reaction was stirred 90 minutes, followed by the slowaddition of 2-fluoro-N-methoxy-N-methyl-benzamide (140 mg, 750 mmol).The reaction was stirred overnight, during which the ice-bath warmed toroom temperature. The following day, the reaction was quenched with asmall quantity of MeOH and the solvents evaporated in vacuo. The residuewas subsequently treated with 4.0M HCl (in dioxane) (1 mL, 4.0 mmol) andH₂O (0.33 mL), and then stirred at 80° C. for two hours. The resultantsolution was diluted with EtOAc, washed with water, saturated sodiumbicarbonate, and brine; dried with MgSO₄, and evaporated employingreduced pressure. The crude sulfonamide was finally purified viapreparatory TLC (20% EtOAc/hexanes) and recrystallization from MeCN/H₂Oto afford 98 mg of the title compound: ¹H NMR (400 MHz, CDCl₃) δ 10.6(s, 1H), 8.3 (d, 1H), 8.2 (d, 1H), 7.74 (d, 2H), 7.6 (d, 1H), 7.5 (d,1H), 7.43 (d, 2H), 7.42-7.37 (m, 2H), 1.26 (s, 9H); MS (ES) M+H expect447.1, found 447.5.

Example 49:4-tert-Butyl-N-[5-chloro-2-(4-fluoro-benzoyl)-pyridin-3-yl]-benzenesulfonamide

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask.The flask was evacuated and purged with nitrogen, followed by theaddition of THF (1 mL). The homogeneous mixture was lowered to −5° C.and iPrMgCl (0.33 mL, 2.0M) was added dropwise. Upon completion of theaddition, the reaction was stirred 90 minutes, followed by the slowaddition of 4-fluoro-N-methoxy-N-methyl-benzamide (137 mg, 750 mmol).The reaction was stirred overnight, during which the ice-bath warmed toroom temperature. The following day, the reaction was quenched with asmall quantity of MeOH and the solvents evaporated in vacuo. The residuewas subsequently treated with 4.0M HCl in dioxane (1 mL, 4.0 mmol) andH₂O (0.33 mL), and then stirred at 80° C. for two hours. The resultantsolution was diluted with EtOAc, washed with water, saturated sodiumbicarbonate, and brine; dried with MgSO₄, and evaporated employingreduced pressure. The crude residue was subsequently purified viareverse phase HPLC (Column: Varian Dynamax 250×21.4 mm Microsorb100-8C18, 0.1% TFA/H₂O (Eluent A): 0.1% TFA/MeCN (Eluent B)): ¹H NMR (400MHz, CDCl₃) δ 10.63 (bs, 1H), 8.29 (d, 1H), 8.20 (d, 1H), 7.85-7.91 (m,2H), 7.74 (d, 2H), 7.42 (d, 2H), 7.09 (t, 2H), 1.25 (s, 9H); MS (ES)M+Na expect 469.1, found 469.4.

Example 50:4-tert-Butyl-N-[5-chloro-2-(3-methoxy-benzoyl)-pyridin-3-yl]-benzenesulfonamide

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask.The flask was evacuated and purged with nitrogen, followed by theaddition of THF (1 mL). The homogeneous mixture was lowered to −5° C.and iPrMgCl (0.33 mL, 2.0M) was added dropwise. Upon completion of theaddition, the reaction was stirred 90 minutes, followed by the slowaddition of 3,N-dimethoxy-N-methyl-benzamide (146 mg, 750 mmol). Thereaction was stirred overnight, during which the ice-bath warmed to roomtemperature. The following day, the reaction was quenched with a smallquantity of MeOH and the solvents evaporated in vacuo. The residue wassubsequently treated with 4.0M HCl in dioxane (1 mL, 4.0 mmol) and H₂O(0.33 mL), and then stirred at 80° C. for two hours. The resultantsolution was diluted with EtOAc, washed with water, saturated sodiumbicarbonate, and brine; dried with MgSO₄, and evaporated employingreduced pressure. The crude residue was subsequently purified viareverse phase HPLC (Column: Varian Dynamax 250×21.4 mm Microsorb100-8C18, 0.1% TFA/H₂O (Eluent A): 0.1% TFA/MeCN (Eluent B)): ¹H NMR (400MHz, CDCl₃) δ 10.61 (s, 1H), 8.29 (d, 1H), 8.20 (d, 1H), 7.74 (d, 2H),7.58 (s, 1H), 7.50 (d, 1H), 7.42 (d, 2H), 7.37 (d, 1H), 7.29 (t, 1H),2.40 (s, 3H), 1.25 (s, 9H); MS (ES) M+H expect 459.1, found 459.5.

Example 51:4-tert-Butyl-N-[5-chloro-2-(3-methanesulfonyl-benzoyl)-pyridin-3-yl]-benzenesulfonamide

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(500 mg, 1.12 mmol) was placed in a dry 2-neck 50 mL round-bottom flask.The flask was evacuated and purged with nitrogen, followed by theaddition of THF (5.6 mL). The homogeneous mixture was lowered to −5° C.and iPrMgCl (1.28 mL, 2.0M) was added dropwise. Upon completion of theaddition, the reaction was stirred 90 minutes, followed by the slowaddition of N-methoxy-N-methyl-3-methylsulfanyl-benzamide (471 mg, 2.23mmol). The reaction was stirred overnight, during which the ice-bathwarmed to room temperature. The following day, the reaction was quenchedwith a small quantity of MeOH and the solvents evaporated in vacuo. Theresidue was subsequently treated with 4.0M HCl in dioxane (4.76 mL, 19.0mmol) and H₂O (1.59 mL), and then stirred at 80° C. overnight. Thefollowing day, the organics were removed in vacuo and the residue wasdiluted with EtOAc. The resultant organics were washed with water,saturated sodium bicarbonate, and brine; dried with MgSO₄, andevaporated employing reduced pressure. The crude residue wassubsequently purified via automated flash chromatography to afford thedesired arylthioether. To a stirring solution of the thioether (100 mg,0.211 mmol) in methylene chloride (0.8 mL) was added mCPBA (77% maximum)(141 mg, 0.632 mmol), during which the exothermic reaction caused slightboiling of the methylene chloride. Upon stirring 30 min, the reactionwas quenched with aqueous sodium metabisulfite and then stirred afurther 15 min. The solution was diluted with EtOAc and the combinedorganics were washed with sodium metabisulfite and saturated sodiumbicarbonate. The organic layer was then dried with MgSO₄ andconcentrated in vacuo to generate the desired arylmethylsulfone: ¹H NMR(400 MHz, CDCl₃) δ 10.86 (s, 1H), 8.43 (dd, 1H), 8.27 (d, 1H), 8.22 (d,1H), 8.11 (dd, 2H), 7.80 (d, 2H), 7.65 (t, 1H), 7.48 (d, 2H), 3.18 (s,3H), 1.27 (s, 9H); MS (ES) M+H expect 507.1, found 507.5.

Example 52:N-[2-(3-Amino-benzoyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(3.84 g, 8.57 mmol) was placed in a dry 2-neck 250 mL round-bottomflask. The flask was evacuated and purged with nitrogen, followed by theaddition of THF (43 mL). The homogeneous mixture was lowered to −5° C.and iPrMgCl (9.86 mL, 2.0M) was added dropwise. Upon completion of theaddition, the reaction was stirred 90 minutes, followed by the slowaddition of N-methoxy-N-methyl-3-nitro-benzamide (4.50 g, 21.43 mmol).The reaction was stirred overnight, during which the ice-bath warmed toroom temperature. The following day, the reaction was quenched with asmall quantity of MeOH and the solvents evaporated in vacuo. The residuewas subsequently treated with 4.0M HCl in dioxane (36 mL, 146 mmol) andH₂O (12 mL), and then stirred at 80° C. overnight. The following day,the organics were removed in vacuo and the residue was diluted withEtOAc. The resultant organics were washed with water, saturated sodiumbicarbonate, and brine; dried with MgSO₄, and evaporated employingreduced pressure. The crude residue was subsequently purified viaautomated flash chromatography to afford the desired nitroarene. To arapidly stirring solution of iron (274 mg, 5.07 mmol) in acetic acid (5mL) at 80° C. was added dropwise a homogeneous solution of thenitroarene (685 mg, 1.45 mmol) in AcOH/CH₂Cl₂ (8 mL/2 mL). The reactionwas stirred 60 min, cooled to ambient temperature, diluted with EtOAc(12 mL), and filtered through celite. The filtrate was washed thoroughlywith EtOAc and concentrated in vacuo. The resultant residue wasdissolved in EtOAc, washed two times with saturated NaHCO₃, dried withsodium sulfate, and concentrated at reduced pressure to afford the crudeaniline: ¹H NMR (400 MHz, CDCl₃) δ 10.54 (s, 1H), 8.28 (d, 1H), 8.19 (d,1H), 7.72 (d, 2H), 7.40 (d, 2H), 7.16 (t, 1H), 7.08 (ddd, 1H), 7.04(ddd, 1H), 6.85 (ddd, 1H), 3.78 (bs, 2H), 1.25 (s, 9H); MS (ES) M+Hexpect 444.1, found 444.1.

Example 53:4-tert-Butyl-N-[5-chloro-2-(3-methanesulfonylamino-benzoyl)-pyridin-3-yl]-benzenesulfonamide

To a stirring solution ofN-[2-(3-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide(60 mg, 0.135 mmol) in pyridine (0.2 mL) was added methanesulfonylchloride (0.012 mL, 0.163 mmol). The homogeneous reaction was stirredovernight to generate a mixture of mono- and bis-sulfonamide. Theresultant solution was partitioned with EtOAc/10% HCl, and the organicswere washed with 10% HCl and saturated sodium bicarbonate. The organiclayer was then dried with sodium sulfate and concentrated in vacuo toproduce the crude sulfonamide mixture that co-eluted via bothreverse-phase and normal-phase chromatography. A 5 mL flask was chargedwith the resultant sulfonamide mixture, tetrabutylammonium fluoride(0.405 mL, 1.0M), and THF (1.3 mL). The reaction was stirred 90 min andthen partitioned with EtOAc/10% HCl. The organics were washed with 10%HCl and saturated sodium bicarbonate, dried with sodium sulfate, andconcentrated in vacuo to produce the desired mono-sulfonamide which wasfurther purified through automated normal-phase chromatography: ¹H NMR(400 MHz, CDCl₃) δ 10.71 (bs, 1H), 8.27 (d, 1H), 8.20 (d, 1H), 7.79 (d,2H), 7.69-7.71 (m, 1H), 7.60-7.62 (m, 1H), 7.42-7.49 (m, 4H), 6.48 (bs,1H), 3.06 (s, 3H), 1.28 (s, 9H); MS (ES) M+H expect 522.1, found 522.1.

Example 54:N-{3-[3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carbonyl]-phenyl}-acetamide

To a stirring solution ofN-[2-(3-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide(60 mg, 0.135 mmol), pyridine (0.022 mL, 0.271 mmol), and methylenechloride (0.68 mL) at 0° C. was added acetyl chloride (0.011 mL, 0.149mmol). The homogeneous reaction was stirred 90 min, diluted with EtOAc,and then quenched with 10% HCl. The organics were washed with 10% HCland saturated sodium bicarbonate, dried with sodium sulfate, andconcentrated in vacuo to produce the target aryl acetamide: ¹H NMR (400MHz, CDCl₃) δ 10.71 (bs, 1H), 8.28 (d, 1H), 8.18 (d, 1H), 7.88-7.91 (m,1H), 7.79 (d, 1H), 7.74 (d, 2H), 7.50 (d, 1H), 7.43 (d, 2H), 7.36 (t,1H), 7.22 (bs, 1H), 2.18 (s, 3H), 1.25 (s, 9H); MS (ES) M+H expect486.1, found 486.5.

Example 55:4-tert-Butyl-N-[5-chloro-2-(6-hydroxy-pyridine-3-carbonyl)-pyridin-3-yl]-benzenesulfonamide

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(2.00 g, 4.46 mmol) was placed in a dry 2-neck 50 mL round-bottom flask.The flask was evacuated and purged with nitrogen, followed by theaddition of THF (15 mL). The homogeneous mixture was lowered to −5° C.and iPrMgCl (5.13 mL, 2.0M) was added dropwise. Upon completion of theaddition, the reaction was stirred 90 minutes, followed by the slowaddition of 6-chloro-N-methoxy-N-methyl-nicotinamide (1.44 g, 7.14mmol). The reaction was stirred overnight, during which the ice-bathwarmed to room temperature. The resultant solution was quenched with 10%HCl and diluted with EtOAc. The organics were washed with 10% HCl andsaturated sodium bicarbonate, dried with sodium sulfate, concentrated invacuo, and purified via automated silica gel chromatography to affordthe diaryl ketone (1.049 g) in 46% yield. A microwave flask was chargedwith the diaryl ketone (40 mg, 0.078 mmol), HCl in dioxane (0.335 mL,4.0M), and water (0.12 mL). The reaction vessel was subjected to amicrowave reaction at 90° C. for 10 min. The reaction was incomplete,thus the vessel was reacted a further 10 min at 120° C., during whichthe starting materials were consumed. The crude mixture was diluted withEtOAc and neutralized to pH 7-8 with saturated sodium bicarbonate. Theorganics were washed with saturated sodium bicarbonate, dried withsodium sulfate, concentrated in vacuo, and purified via automated columnchromatography to generate a mixture of the desired4-tert-butyl-N-[5-chloro-2-(6-hydroxy-pyridine-3-carbonyl)-pyridin-3-yl]-benzenesulfonamideand4-tert-butyl-N-[5-chloro-2-(6-chloro-pyridine-3-carbonyl)-pyridin-3-yl]-benzenesulfonamide:¹H NMR (400 MHz, CDCl₃) δ 10.98 (bs, 1H), 8.70 (d, 1H), 8.29 (d, 1H),8.16-8.20 (m, 2H), 7.76 (d, 2H), 7.45 (d, 2H), 6.59 (d, 1H), 1.27 (s,9H); MS (ES) M+H expect 446.1, found 446.3.

Example 56:4-tert-Butyl-N-[5-chloro-2-(6-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-benzenesulfonamide

To a stirring solution of4-tert-butyl-N-[5-chloro-2-(6-chloro-pyridine-3-carbonyl)-pyridin-3-yl]-benzenesulfonamide(30 mg, 0.065 mmol) in MeOH (0.65 mL) was added NaOMe (18 mg, 0.324mmol). The resultant solution was heated to 80° C. and stirred 4 h. Thereaction was quenched with 10% HCl (to pH 6-7), diluted with EtOAc, andthe pH adjusted to 7-8 with saturated sodium bicarbonate. The organicswere washed with saturated sodium bicarbonate, dried with sodiumsulfate, concentrated in vacuo, and purified via automated flashchromatography to produce the target methoxy pyridine: ¹H NMR (400 MHz,CDCl₃) δ 10.71 (bs, 1H), 8.72 (d, 1H), 8.26 (d, 1H), 8.08-8.20 (m, 2H),7.72 (d, 2H), 7.37 (d, 2H), 6.75 (d, 1H), 4.00 (s, 3H), 1.23 (s, 9H); MS(ES) M+H expect 460.1, found 460.2.

Example 57:N-[2-(6-Amino-pyridine-3-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide

A sealed tube was charged with4-tert-butyl-N-[5-chloro-2-(6-chloro-pyridine-3-carbonyl)-pyridin-3-yl]-benzenesulfonamide(320 mg, 0.631 mmol), concentrated ammonium hydroxide (3.2 mL), and THF(3.2 mL). The tube was sealed and stirred for 3 days at 100° C. Thesolvents were subsequently removed in vacuo and the residue purified byautomated flash chromatography to provide the desired aminopyridine: ¹HNMR (400 MHz, CDCl₃) δ 10.72 (bs, 1H), 8.69 (d, 1H), 8.28 (dd, 1H), 8.16(dd, 1H), 8.02 (dd, 1H), 7.71 (d, 2H), 7.40 (d, 2H), 6.46 (d, 1H), 5.00(bs, 2H), 1.24 (s, 9H); MS (ES) M+H expect 445.1, found 445.1.

Example 58:4-tert-Butyl-N-[5-chloro-2-(2-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-benzenesulfonamide

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask.The flask was evacuated and purged with nitrogen, followed by theaddition of THF (1 mL). The homogeneous mixture was lowered to −5° C.and iPrMgCl (0.33 mL, 2.0M) was added dropwise. Upon completion of theaddition, the reaction was stirred 90 minutes, followed by the slowaddition of N-methoxy-2,N-dimethyl-nicotinamide (135 mg, 750 mmol). Thereaction was stirred overnight, during which the ice-bath warmed to roomtemperature. The following day, the reaction was quenched with a smallquantity of MeOH and the solvents evaporated in vacuo. The residue wassubsequently treated with 4.0M HCl in dioxane (1 mL, 4.0 mmol) and H₂O(0.33 mL), and then stirred at 80° C. for two hours. The resultantsolution was diluted with EtOAc, washed with water, saturated sodiumbicarbonate, and brine; dried with MgSO₄, and evaporated employingreduced pressure. The crude residue was subsequently purified viaautomated flash chromatography to afford the desired sulfonamide: ¹H NMR(400 MHz, CDCl₃) δ 10.9 (s, 1H), 8.58 (d, 1H), 8.22 (d, 2H), 7.81 (d,2H), 7.53-7.46 (m, 3H), 7.20-7.14 (m, 1H), 2.30 (s, 3H), 1.31 (s, 9H);MS (ES) M+H expect 444.1, found 444.5.

Example 59: (3-Amino-5-chloropyridin-2-yl)(3-fluorophenyl)methanone

Step 1

A freshly oven dried 250 mL round-bottom flask was charged with2-iodo-3-nitro-5-chloro-pyridine (1.41 g, 5.0 mmol). The resultantsolution was cooled to −78° C. under N₂ and PhMgCl (2M, 3 mL, 6.0 mmol)added and then stirred at the same temperature for 30 min.3-Fluorobenzaldehyde (1.24 g, 10 mmol) was added and the resultingmixture stirred at −78° C. for two hours and then at room temperaturefor 24 h. The reaction was quenched with NH₄Cl (sat), extracted withEtOAc, washed with brine, dried over MgSO₄, and concentrated underreduced pressure. The residue was further purified through automatednormal-phase chromatography to afford5-chloro-3-nitropyridin-2-yl)(3-fluorophenyl)methanol (560 mg, 40%)which was used directly for the next step: ¹H NMR (400 MHz, CDCl₃) δ8.85 (d, 1H), 8.37 (d, 1H), 7.23 (m, 1H), 7.06 (dd, 1H), 6.95 (dd, 1H),6.43 (d, 2H), 4.99 (d, 1H); MS (ES) (M⁺−OH) expect 265.0, found 265.1.

Step 2

A 50 mL round-bottom flask was charged with the above alcohol (500 mg,1.78 mmol) and dichloromethane (10 mL). To the resultant solution wasadded Dess-Martin periodinane (900 mg, 2.13 mmol) and stirred at theroom temperature for 30 min. The reaction was quenched with NaS₂O₃,filtered through celite, and extracted with EtOAc, washed with brine,dried over MgSO₄, and concentrated under reduced pressure to afford thecrude nitro ketone (500 mg, quantitative) which was used directly forthe next step: ¹H NMR (400 MHz, CDCl₃) δ 8.87 (d, 1H), 8.50 (s, 1H),7.53 (m, 2H), 7.44 (m, 1H), 7.33 (m, 1H); MS (ES) (M⁺+H) expect 281.0,found 281.1.

Step 3

A 50 mL round-bottom flask was charged with the iron powder (336 mg, 6.0mmol) in acetic acid (10 mL) and heated to 80° C. (oil bath) under N₂.To this mixture was added slowly the nitroketone (500 mg, 1.78 mmol) inacetic acid (5 mL) via dropping funnel and stirred at 80° C. for another30 min after the addition. After cooling the reaction mixture, it wasdiluted with EtOAc, filtered through celite and the solvent evaporatedin vacuo. The residue was dissolved in EtOAc and washed with saturatedNaHCO₃, brine, dried over MgSO₄, and concentrated under reducedpressure. The residue was purified through automated normal-phasechromatography to afford3-amino-5-chloropyridin-2-yl)(3-fluorophenyl)methanone (430 mg, 97%)which was used directly for the next step: ¹H NMR (400 MHz, CDCl₃) δ7.93 (d, 1H), 7.70-7.62 (m, 1H), 7.40 (m, 1H), 7.20 (m, 1H), 7.09 (d,1H), 6.26 (br s, 2H); MS (ES) (M⁺+H) expect 251.0, found 251.0.

Example 60: 6-isopropoxypyridine-3-sulfonyl Chloride

Step 1

A freshly oven dried 500 mL round-bottom flask was charged with2-chloro-5-nitropyridine (5.0 g, 31.6 mmol) and anhydrous iPrOH (50 mL).The resultant solution was cooled in an ice bath and iPrONa (50 mmol) iniPrOH (250 mL) added slowly, followed by stirring at the sametemperature for 30 min and then at room temperature for 14 h. Thereaction was quenched with H₂O (5 mL), filtered through celite, andconcentrated under reduced pressure. The residue was diluted with EtOAcand washed with brine, dried over MgSO₄, and concentrated under reducedpressure. The residue was purified through automated normal-phasechromatography to afford 2-isopropoxyl-5-nitropyridine (4.6 g, 79%)which was used directly for the next step: ¹H NMR (400 MHz, CDCl₃) δ9.02 (d, 1H), 8.30 (dt, 1H), 6.75 (d, 1H), 5.40 (sep, 1H), 1.38 (d, 6H);MS (ES) (M⁺+H) expect 183.1, found 183.1.

Step 2

A 100 mL round-bottom flask was charged with the iron powder (5.6 g, 10mmol) in acetic acid (30 mL) and heated to 80° C. (oil bath) under N₂.To this mixture was added slowly the above 2-isopropoxyl-5-nitropyridine(4.6 g, 25.2 mmol) in acetic acid (30 mL) via dropping funnel and thereaction stirred at 80° C. for another 30 min after the addition. Aftercooling the reaction mixture, it was diluted with EtOAc, filteredthrough celite, and the solvent evaporated in vacuo. The residue wasdissolved in EtOAc and washed with NaHCO₃ (sat.), brine, dried overMgSO₄, and concentrated under reduced pressure. The residue was purifiedthrough automated normal-phase chromatography to afford2-isopropoxyl-5-aminopyridine (3.8 g, 99%) which was used directly forthe next step: ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, 1H), 7.00 (dt, 1H),6.52 (d, 1H), 5.10 (sep, 1H), 1.30 (d, 6H); MS (ES) (M⁺+H) expect 153.1,found 153.1.

Step 3

A 50 mL round-bottom flask was charged with2-isopropoxyl-5-aminopyridine (1.6 g, 10.5 mmol), hydrochloric acid(conc.) (10 mL) and glacial acetic acid (8 mL) and cooled to −10° C. Tothis mixture was added slowly a solution of NaNO₂ (828 mg, 12 mmol) inH₂O (2 mL) and the reaction stirred at −10° C. for another 30 min afterthe addition. In a second flask, sulfur dioxide was bubbled into amagnetically stirred acetic acid (16 mL) to saturation. Cuprous chloride(250 mg) was added and the introduction of sulfur dioxide was continueduntil the yellow-green suspension became blue-green. The mixture wasthen cooled to −10° C. The diazonium salt mixture was added in portions(gas evolution) and the temperature was kept under −5° C. The darkmixture was kept at −10° C. for 30 min and then at −5° C. for 1 h. Themixture was poured to ice water and extracted with ether, washed withNaHCO₃ (sat.) until the washings were neutral, then with cold water,dried over MgSO₄, and concentrated under reduced pressure to afford6-isopropoxypyridine-3-sulfonyl chloride (1.5 g, 64%) which was useddirectly for the next step: ¹H NMR (400 MHz, CDCl₃) δ 8.80 (d, 1H), 8.06(dt, 1H), 6.80 (d, 1H), 5.42 (sep, 1H), 1.38 (d, 6H); MS (ES) (M⁺+H)expect 235.0, found 235.1.

Example 61:N-(5-chloro-2-(3-fluorobenzoyl)pyridin-3-yl)-4-isopropoxybenzenesulfonamide

A 25 mL round-bottom flask was charged with(3-amino-5-chloropyridin-2-yl)(3-fluorophenyl)methanone (130 mg, 0.52mmol), 6-isopropoxypyridine-3-sulfonyl chloride (130 mg, 0.55 mmol),pyridine (2 mL) and dichloromethane (2 mL). The resultant solution washeated to 70° C. and stirred for 15 h. The pyridine was removed in vacuoand THF (5 mL) and 4.0N NaOH (2 mL) were added. The mixture was stirredat 60° C. for 24 h. The solvent was subsequently removed in vacuo andthe residue was diluted with water (5 mL) and the pH was adjusted to 6-7with 10% HCl. The resultant aqueous solution was extracted with EtOAc,washed with brine, dried over MgSO₄, and concentrated under reducedpressure. The residue was purified through automated normal-phasechromatography to affordN-(5-chloro-2-(3-fluorobenzoyl)pyridin-3-yl)-4-isopropoxybenzenesulfonamide(60 mg, 26%): ¹H NMR (400 MHz, CDCl₃) δ 10.62 (s, 1H), 8.58 (d, 1H),8.32 (d, 1H), 8.18 (d, 1H), 7.86 (dd, 1H), 7.60 (dd, 1H), 7.52 (dt, 1H),7.40 (m, 1H), 7.30 (dd, 1H), 6.60 (d, 1H), 5.30 (sep, 1H), 1.30 (d, 1H);MS (ES) (M⁺+2H) expect 250.0, found 250.1.

Example 62:N-(2-Benzoyl)-5-chloro-pyridin-3-yl)-4-isopropoxybenzenesulfonamide

Step 1

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-isopropoxyl-N-methoxymethyl-benzenesulfonamide(450 mg, 1.0 mmol) was placed in a dry 100 mL round-bottom flask sealedwith septa. The flask was evacuated and purged with nitrogen, followedby the addition of dry THF (30 mL). The homogeneous solution was cooledto 0° C. and iPrMgCl (1.5 mL, 2.0M) was added dropwise. Upon completionof the addition, the mixture was stirred at 0° C. for 90 min, followedby the slow addition of N-methoxy-N-methyl-benzamide (660 mg, 4.0 mmol).The reaction mixture was stirred at 0° C. for 2 h and then at roomtemperature overnight. The reaction was quenched with NH₄Cl (sat.) andextracted with EtOAc, washed with brine, dried over MgSO₄, andconcentrated under reduced pressure. The residue was purified throughautomated normal-phase chromatography to afford MOM-protectedsulfonamide (360 mg, 76%) which was used directly for the next step: ¹HNMR (400 MHz, CDCl₃) δ 8.55 (d, 1H), 7.78 (m, 3H), 7.58 (d, 2H), 7.52(t, 1H), 7.42 (d, 2H), 7.33 (t, 2H), 6.55 (d, 2H), 5.20 (s, 2H), 4.33(sep, 1H), 3.47 (s, 3H), 1.27 (d, 6H); MS (ES) (M++Na) expect 497.1,found 497.1.

Step 2

The above MOM-protected sulfonamide (400 mg, 0.84 mmol) was treated with4.0M HCl in dioxane (4 mL, 16 mmol) and H₂O (2 mL), and then stirred at80° C. for 1.5 h. The mixture was diluted with EtOAc. The resultantorganics were washed with NaHCO₃ (sat.), and brine; dried (MgSO₄), andconcentrated under reduced pressure and was purified through automatednormal-phase chromatography to affordN-(2-benzoyl)-5-chloro-pyridin-3-yl)-4-isopropoxybenzenesulfonamide: ¹HNMR (400 MHz, CDCl₃) (10.54 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.73(m, 4H), 7.55 (t, 1H), 7.40 (t, 2H), 6.80 (d, 2H), 4.33 (sep, 1H), 1.27(d, 6H); MS (ES) (M+H) expect 431.1, found 431.1.

Step 63:N-(2-Benzoyl)-5-chloro-pyridin-3-yl)-4-tert-butyl-benzenesulfonamide

Step 1

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(450 mg, 1.0 mmol) was placed in a dry 100 mL round-bottom flask sealedwith septa. The flask was evacuated and purged with nitrogen, followedby the addition of dry THF (30 mL). The homogeneous solution was cooledto 0° C. and iPrMgCl (1.5 mL, 2.0M) was added dropwise. Upon completionof the addition, the mixture was stirred at 0° C. for 90 min, followedby the slow addition of N-methoxy-N-methyl-benzamide (660 mg, 4.0 mmol).The reaction mixture was stirred at 0° C. for 2 h and then at roomtemperature overnight. The reaction was quenched with NH₄Cl (sat.) andextracted with EtOAc, washed with brine, dried over MgSO₄, andconcentrated under reduced pressure. The residue was purified throughautomated normal-phase chromatography to afford MOM-protectedsulfonamide (360 mg, 76%) which was used directly for the next step: ¹HNMR (400 MHz, CDCl₃) b 8.55 (d, 1H), 7.65 (m, 3H), 7.50 (m, 3H), 7.37(t, 2H), 7.24 (d, 2H), 5.20 (s, 2H), 3.45 (s, 3H), 1.19 (s, 9H); MS (ES)(M++Na) expect 495.1, found 495.1.

Step 2

The above MOM-protected sulfonamide (340 mg, 0.72 mmol) was treated with4.0M HCl in dioxane (4 mL, 16 mmol) and H₂O (2 mL), and then stirred at80° C. for 1.5 h. The mixture was diluted with EtOAc. The resultantorganics were washed with NaHCO₃ (sat.), and brine; dried (MgSO₄),concentrated under reduced pressure, and purified through automatednormal-phase chromatography to affordN-(2-benzoyl)-5-chloro-pyridin-3-yl)-4-tert-butyl-benzenesulfonamide: ¹HNMR (400 MHz, CDCl₃) δ 10.64 (s, 1H), 8.29 (d, 1H), 8.19 (d, 1H), 7.73(t, 3H), 7.55 (t, 1H), 7.40 (t, 3H), 7.25 (d, 1H), 1.24 (s, 9H); MS (ES)(M⁺+H) expect 429.1, found 429.1.

Example 64:N-(2-bromo-5-chloro-pyridin-3-yl)-4-isopropoxy-N-methoxymethyl-benzenesulfonamide

A 200 mL round-bottom flask was charged with2-bromo-5-chloro-pyridin-3-ylamine (2.06 g, 9.94 mmol),4-isopropoxysulfonyl chloride (3.5 g, 14.91 mmol), and pyridine (10 mL).The resultant solution was heated to 80° C. and stirred overnight. Thefollowing day, the pyridine was removed in vacuo and THF (20 mL) and4.0N NaOH (30 mL) were added and the reaction was stirred at 60° C. for72 hours. The organics were subsequently removed in vacuo and theresidues were diluted with water (100 mL). The small quantity ofinsoluble solid was removed by filtration and the pH was adjusted to 6-7with concentrated HCl. The resultant precipitate was filtered and washedwith water to afford the diarylsulfonamide (3.44 g) in 85% yield. To asolution of the crude sulfonamide (3.41 g, 8.41 mmol) and K₂CO₃ (4.65 g,33.64 mmol) in anhydrous THF (21 mL) was added chloromethyl methyl ether(1.3 mL, 16.81 mmol). The resultant heterogeneous solution was stirredovernight at ambient temperature and the solids were subsequentlyremoved via filtration. The filtrate was then removed in vacuo toproduce the desired product as a light yellowish solid (3.54 g, 94%yield).

Example 65:N-[5-chloro-2-(2-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-4-isopropoxy-benzenesulfonamide

N-(2-bromo-5-chloro-pyridin-3-yl)-4-isopropoxy-N-methoxymethyl-benzenesulfonamide(592 mg, 1.32 mmol) was placed in a dry 25 mL round-bottom flask. Theflask was evacuated and purged with nitrogen, followed by the additionof THF (5 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl(1.72 mL, 2.0M) was added dropwise. Upon completion of the addition, thereaction was stirred 60 minutes, followed by the addition ofN-methoxy-2,N-dimethyl-nicotinamide (379 mg, 2.11 mmol). The reactionwas stirred overnight, during which the ice-bath warmed to roomtemperature. The following day, the reaction was quenched with a smallquantity of MeOH and the solvents evaporated in vacuo. The residue wassubsequently treated with 4.0M HCl in dioxane (6 mL, 24.0 mmol) and H₂O(6.0 mL), and then stirred at 80° C. for two hours. The resultantsolution was concentrated in vacuo and saturated sodium bicarbonate wasadded to adjust to neutral pH. The solution was extracted with ethylacetate, dried over magnesium sulfate, filtered and concentrated invacuo. The crude sulfonamide was finally purified via automated flashchromatography to afford the title compound: ¹H NMR (400 MHz, CDCl₃) δ10.90 (s, 1H), 8.58 (d, 1H), 8.17 (m, 2H), 7.80 (d, 2H), 7.49 (d, 1H),7.16 (m, 1H), 6.89 (d, 2H), 4.57 (sep, 1H), 2.34 (s, 3H), 1.33 (d, 6H);MS (ES) M+H expect 445.9, found 446.1.

Example 66:N-[5-Chloro-2-(3-fluoro-benzoyl)-pyridin-3-yl]-4-isopropoxy-benzenesulfonamide

N-(2-Bromo-5-chloro-phenyl)-4-isopropoxy-N-methoxymethyl-benzenesulfonamide(300 mg, 0.67 mmol) was placed in a dry 25 mL round-bottom flask. Theflask was evacuated and purged with nitrogen, followed by the additionof THF (3 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl(0.87 mL, 2.0M) was added dropwise. Upon completion of the addition, thereaction was stirred 60 minutes, followed by the addition of3-fluoro-N-methoxy-N-methyl-benzamide (196 mg, 1.1 mmol). The reactionwas stirred overnight, during which the ice-bath warmed to roomtemperature. The following day, the reaction was quenched with a smallquantity of MeOH and the solvents evaporated in vacuo. The residue wassubsequently treated with 4.0M HCl in dioxane (3 mL, 12.0 mmol) and H₂O(1 mL), and then stirred at 80° C. overnight. The resultant solution wasconcentrated in vacuo and saturated sodium bicarbonate was added toadjust to neutral pH. The solution was extracted with ethyl acetate,dried over magnesium sulfate, filtered and concentrated in vacuo. Thecrude sulfonamide was finally purified via automated flashchromatography to afford the title compound: ¹H NMR (400 MHz, CDCl₃) δ10.50 (s, 1H), 8.28 (d, 1H), 8.17 (d, 1H), 7.20 (d, 2H), 7.59 (d, 1H),7.47 (m, 1H), 7.39 (m, 1H), 7.26 (m, 1H), 6.83 (d, 2H), 4.53 (sep, 1H),1.32 (d, 6H); MS (ES) M+H expect 449.9, found 449.2.

Example 67: 4-Chloro-3-methylsulfonylchloride

Iron powder (150 g, 2.68 mol) and AcOH (600 mL) were charged into a 2 Lround bottom flask equipped with a mechanical stirrer and thermometer.The mixture as warmed to 80° C. 4-Chloro-3-methylnitrobenzene (150 g,0.87 mol) in AcOH (200 mL) was added slowly to the flask over 4 h,keeping the reaction temperature below 90° C. Upon consumption of thereactants, the mixture was filtered through a pad of Celite and thefilter cake was washed with methanol (200 mL). The filtrate wasconcentrated and the residue was poured into 1.5 L of ice water (1:1)and the resulting precipitate was filtered. The crude product wasdissolved in 300 mL 6N HCl in water/dioxane (1:1) and stirred at 100° C.for 3 h. It was then cooled to room temperature and the precipitate wasfiltered and dried to provide 130 g of 4-chloro-3-methyl-phenylaminehydrochloride as a colorless powder.

4-Chloro-3-methylaniline hydrochloride (75 g, 0.54 mol) was dissolved in200 mL concentrated hydrochloride acid (200 mL) and acetic acid (60 mL).The mixture was cooled to −5° C. and NaNO₂ (40.9 g, 0.59 mmol) wasadded. The mixture was stirred between −10° C. to −5° C. for 1 h. Whilethe diazotization was in progress, glacial AcOH (600 mL) was placed in a4000-mL beaker and stirred magnetically. Sulfur dioxide was introducedby a bubbler tube with a fritted end immersed below the surface of theAcOH until saturation was evident. Cuprous chloride (15 g) was added tothe solution. The introduction of sulfur dioxide was continued until theyellow-green suspension becomes blue-green. The mixture was then placedin an ice bath and cooled to 10° C. The diazotization reaction mixturewas subsequently added in portions over a 30 min period to the sulfurdioxide solution, ensuring the temperature of the solution did notexceed 30° C. After all the diazonium salt mixture was added, themixture was poured into ice water (2 L). The resulting precipitate wasfiltered and re-dissolved in hexane (500 mL). The mixture was filteredthrough a pad of silica gel (100 g) and the filter pad was washed withhexane (300 mL). The combined filtrate was concentrated to yield 50 g of4-chloro-3-methylbenzenesulfonyl chloride as slightly yellow solid.

Example 68:N-(2-Bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution of 2-bromo-5-chloro-pyridin-3-ylamine (2.07 g,10.0 mmol) in anhydrous pyridine (20 mL) was added3-(trifluoromethyl)benzenesulfonyl chloride (4.90 g, 20.0 mmol) and theprogress of the reaction was followed by LCMS. The reaction mixture wasstirred overnight (18 h), then concentrated to dryness. The residue wasdissolved in THF (20 mL) and stirred 18 h with 1M TBAF (20 mL) in THF tocleave the bis-sulfonamide. The THF was subsequently evaporated and theresidue was dissolved in ethyl acetate. The organic phase was thenwashed with water (2×100 mL), brine, and then dried (MgSO₄), filtered,and concentrated under reduced pressure. The residue was purified bychromatography on silica gel using ethyl acetate-hexane to provideN-(2-Bromo-5-chloro-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamideas a white crystalline solid. MS m/z 417.1 (M+H).

Methoxymethyl chloride (720 mg, 8.94 mmol) was added dropwise to amixture ofN-(2-bromo-5-chloro-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide(2.51 g, 6.04 mmol) and potassium carbonate (5.1 g) in THF (60 mL) atroom temperature. After 5 h, the potassium salts removed by vacuumfiltration, and the filtrate was concentrated under reduced pressure.The residual light yellow solid was chromatographed on silica gel usingethyl acetate-hexane to provideN-(2-bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideas white crystals. MS m/z 461.2 (M+H).

Example 69:N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-methyl-benzenesulfonamide

To a stirred solution of 2-bromo-5-chloro-pyridin-3-ylamine (4.12 g, 20mmol) in anhydrous pyridine (100 mL) was added3-methyl-4-chlorobenzenesulfonyl chloride (6.35 g, 26 mmol) and theprogress of the reaction was followed by LCMS. The reaction mixture wasstirred overnight (18 h), then concentrated to remove as much of thepyridine as possible. The residue was dissolved in THF and was stirred18 h with aqueous sodium hydroxide (20 mL) in THF to cleave thebis-sulfonamide. The reaction mixture was subsequently neutralized withaqueous HCl and extracted with EtOAc; the organic phase was washed withwater (2×100 mL), brine, and then dried (MgSO₄), filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel using EtOAc-hexane to provideN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-methyl-benzenesulfonamideas a white crystalline solid. MS m/z 397.1 (M+H).

Methoxymethyl chloride (1.2 g, 14.3 mmol) was added dropwise to amixture ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-methyl-benzenesulfonamide(5.0 g, 12.7 mmol) and potassium carbonate (3.2 g, 23.2 mmol) in THF (30mL) at room temperature. After 5 h, the potassium salts were removed byvacuum filtration and the filtrate was concentrated under reducedpressure. The residual light yellow solid was chromatographed on silicagel using ethyl acetate-hexane to provide theN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-methyl-benzenesulfonamideas white crystals. MS m/z 441.2 (M+H).

Example 70:4-Chloro-N-[5-chloro-2-(2-ethoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

4-Chloro-N-[5-chloro-2-(2-ethoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidewas prepared from 2-ethoxy-N-methoxy-N-methyl-benzamide andN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideaccording to previously described procedure in example 29. The productwas purified by flash column chromatography on silica gel using ethylacetate-hexane. MS m/z: 562.4 (M+H).

Example 71:4-Chloro-N-[5-chloro-2-(2-ethoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

4-Chloro-N-[5-chloro-2-(2-ethoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidewas hydrolyzed using 4M HCl in dioxane (12 mL) and water (4 mL) at 100°C. to provide4-chloro-N-[5-chloro-2-(2-ethoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide.Product was purified by HPLC. MS m/z 519.1 (M+H).

Example 72:4-Chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-methyl-benzenesulfonamide

4-Chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-methyl-benzenesulfonamidewas prepared fromN-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-methyl-benzenesulfonamideand 2,N-Dimethoxy-6,N-dimethyl-benzamide according to previouslydescribed procedure example 29. The product was purified bychromatography on silica gel using ethyl acetate-hexane. MS m/z: 509.4(M+H).

Example 73:4-Chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-3-methyl-benzenesulfonamide

4-Chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-methyl-benzenesulfonamidewas hydrolyzed using 4M HCl in dioxane (12 mL), and water (4 mL) at 100°C. to provide4-chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-3-methyl-benzenesulfonamide.The product was purified by HPLC. MS m/z: 465.4 (M+H).

Example 74:N-[5-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution ofN-(2-Bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(459 mg, 1.00 mmol) in anhydrous THF (5 mL) at −10° C. was added 2Misopropylmagnesium chloride in THF (1.1 mL, 2.2 mmol) and stirred at thesame temperature for 30 min. 2-Fluoro-6-methoxy-benzaldehyde (308 mg,2.00 mmol) was subsequently added in one portion, and the reactionmixture was warmed to room temperature and stirred overnight (18 h). Itwas then quenched with saturated aqueous NH₄Cl (10 mL), and extractedwith EtOAc (3×75 mL). The combined extracts were washed with aqueousNaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by chromatography on silicagel using ethyl acetate-hexane to provideN-{5-chloro-2-[(2-fluoro-6-methoxy-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.MS m/z 535.4 (M+H).

A mixture ofN-{5-chloro-2-[(2-fluoro-6-methoxy-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(0.38 g) and Dess-Martin reagent (0.90 g, 2.1 mmol) in CH₂Cl₂ (15 mL) atroom temperature was stirred for 5 h. A mixture of 10% aqueous Na₂S₂O₃(10 mL) and saturated aqueous NaHCO₃ (10 mL) was then added and thebiphasic mixture vigorously stirred for 30 min. The organic phase wasthen separated and the aqueous portion was extracted with CH₂Cl₂. Thecombined organic extracts were washed with saturated aqueous NaHCO₃ andbrine, dried (Na₂SO₄), and filtered. The filtrate was concentrated underreduced pressure and the residue purified by chromatography on silicagel using ethyl acetate-hexane to provideN-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.MS m/z 555.1 (M+Na).

Example 75:N-[5-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

N-[5-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(180 mg, 0.313 mmol) was magnetically stirred in water (1.0 mL) and 4NHCl in dioxane (2.5 mL) and heated at 85° C. for 7 h. The reaction wassubsequently concentrated and the residue was neutralized (pH 7) withaqueous sodium bicarbonate and extracted with EtOAc (3×80 mL). Theextracts were dried (MgSO₄), filtered, and chromatographed on silica gelusing EtOAc-hexane (gradient, 0:100 to 50:50) to provideN-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide:MS m/z 489.1 (M+H); 511.0 (M+Na).

Example 76:4-Chloro-N-{2-[(2-fluoro-6-methoxyphenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(158 mg, 0.33 mmol) in THF (3 mL) under nitrogen atmosphere at −30° C.was added isopropylmagnesium chloride (2M solution in THF, 0.4 mL, 0.8mmol) via dropwise addition. The mixture was then stirred for 30 min at0° C. followed by the addition of a solution of2-fluoro-6-methoxy-benzaldehyde (96.6 mg, 0.63 mmol) at −30° C. Themixture was stirred at room temperature for 3 h, quenched with saturatedaqueous NH₄Cl solution (5 mL), and extracted with EtOAc (2×25 mL). Thecombined organic extracts were washed with saturated aqueous NH₄Clsolution (25 mL) and brine (25 mL), dried (Na₂SO₄), and concentratedunder reduced pressure. The obtained residue was purified by flashcolumn chromatography on silica gel (30% EtOAc-hexanes) to obtain4-chloro-N-{2-[(2-fluoro-6-methoxyphenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(110 mg) as yellow syrup in 60% yield. ESMS m/z: 549 (M+H).

Example 77:4-Chloro-N-[2-(2-fluoro-6-methoxy-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution of4-chloro-N-{2-[(2-fluoro-6-methoxyphenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(110 mg, 0.2 mmol) in CH₂Cl₂ (5 mL) was added Dess-Martin periodinane(170 mg, 0.4 mmol) and stirred for 3 h at room temperature. 10% aqueousNa₂S₂O₃ (5 mL) and saturated aqueous NaHCO₃ solution (5 mL) were addedand stirred for 30 min. The aqueous layer was then extracted with EtOAc(2×25 mL). The combined organic extracts were subsequently washed withsaturated aqueous NaHCO₃ solution (20 mL) and brine (20 mL), dried(Na₂SO₄), concentrated to obtain4-chloro-N-[2-(2-fluoro-6-methoxy-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoro-methyl-benzenesulfonamide(85.4 mg) in 78% yield which was used without further purification. MSm/z: 515 (M+H−MeOH), 569 (M+Na).

Example 78:4-Chloro-N-[2-(2-fluoro-6-methoxy-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[2-(2-fluoro-6-methoxy-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoro-methyl-benzenesulfonamide(85 mg, 0.15 mmol) in 4M HCl in dioxane (5 mL) and water (1 mL) wasrefluxed for 3 h. The reaction mixture was cooled to room temperature,evaporated to dryness, and neutralized with saturated aqueous NaHCO₃solution to pH 7-8. The mixture was extracted with EtOAc (2×25 mL),dried (Na₂SO₄), filtered and concentrated. The obtained residue waspurified by flash column chromatography on silica gel (70%EtOAc-hexanes) to afford4-chloro-N-[2-(2-fluoro-6-methoxy-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(55 mg) as an off white solid in 70% yield. MS m/z 503 (M+H).

Example 79:4-Chloro-N-{5-chloro-2-[(2-chloro-6-fluoro-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(246 mg, 0.5 mmol) in THF (3 mL) under nitrogen atmosphere at −30° C.was added isopropylmagnesium chloride (2M solution in THF, 0.6 mL, 1.2mmol) via dropwise addition. The mixture was then stirred for 30 min at0° C. followed by the addition of a solution of2-chloro-6-fluoro-benzaldehyde (150.6 mg, 0.95 mmol) at −30° C. Themixture was stirred at room temperature for 3 h, quenched with saturatedaqueous NH₄Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Thecombined organic layers were washed with saturated aqueous NH₄Clsolution (25 mL) and brine (25 mL), dried (Na₂SO₄), and concentratedunder reduced pressure. The obtained residue was purified by flashcolumn chromatography on silica gel (30% EtOAc-hexanes) to obtain4-chloro-N-{5-chloro-2-[(2-chloro-6-fluoro-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(144 mg) as yellow syrup in 51% yield. MS m/z 573 (M+H).

Example 80:4-Chloro-N-[5-chloro-2-(2-chloro-6-fluoro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution of4-chloro-N-{5-chloro-2-[(2-chloro-6-fluoro-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(144 mg, 0.252 mmol) in CH₂Cl₂ (5 mL) was added Dess-Martin periodinane(213.5 mg, 0.5 mmol) and stirred for 3 h at room temperature. 10%aqueous Na₂S₂O₃ (5 mL) and saturated aqueous NaHCO₃ solution (5 mL) wereadded to the reaction mixture and stirred for 30 min. The aqueous layerwas then extracted with EtOAc (2×25 mL). The combined organic extractswere subsequently washed with saturated aqueous NaHCO₃ solution (20 mL)and brine (20 mL), dried (Na₂SO₄), and concentrated to obtain4-chloro-N-[5-chloro-2-(2-chloro-6-fluoro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(107 mg) in 75% yield which was used without further purification. MSm/z: 539 (M−MeOH+H), 593 (M+Na).

Example 81:4-chloro-N-[5-chloro-2-(2-chloro-6-fluoro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[5-chloro-2-(2-chloro-6-fluoro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(100 mg, 0.17 mmol) in 4M HCl in dioxane (5 mL) and water (1 mL) washeated at reflux for 3 h. The reaction mixture was cooled to roomtemperature, evaporated to dryness, and neutralized with saturatedaqueous NaHCO₃ solution to pH 7-8. The mixture was extracted with EtOAc(2×25 mL), dried (Na₂SO₄), filtered and concentrated. The residual solidwas purified by flash column chromatography (70% EtOAc-hexanes) onsilica gel to afford4-chloro-N-[5-chloro-2-(2-chloro-6-fluoro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(62 mg) as an off white solid in 67% yield. MS m/z: 527 (M+H), 549(M+Na).

Example 82:4-Chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution of n-BuLi in hexane (0.69 mL, 1.1 mmol, 1.6M solution inhexane) under N₂ atm at −20° C. was added a solution of2,2,6,6-tetramethyl piperidine (TMP, 187 μL) in THF (1 mL). The mixturecooled to −50° C. and a solution of 3-chlorobenzoic acid (78.3 mg, 0.5mmol) in THF (0.5 mL) was added. The resulting reaction mixture wasstirred at −50° C. for 4 h and treated slowly with4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(884 mg, 2.0 mmol) in THF (1 mL), warmed to room temperature and stirredfor 2 h. The reaction mixture was slowly poured in ice cold water (10mL), and ether was added. The bilayer was separated and the aqueousportion was washed with diethyl ether (2×25 mL) and separated. Theaqueous layer was acidified with 4N HCl solutions to pH 2 and extractedwith diethyl ether (2×25 mL). The combined organic extracts were dried(Na₂SO₄), filtered and evaporated. The residual solid was dissolved inCH₂Cl₂ (5 mL), treated with p-toluenesulfonic acid monohydrate (100 mg),and stirred at room temperature for 2 h. The reaction mixture wasconcentrated and purified by flash chromatography (25% EtOAc in hexanes)to obtain4-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(77 mg) in 26.6% yield. MS m/z: 581 (M+H).

Example 83:4-Chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzene-sulfonamide(77 mg, 0.13 mmol) in 4M HCl in dioxane (3 mL) and water (1 mL) washeated at reflux for 3 h. The reaction mixture was then cooled to roomtemperature, evaporated to dryness and neutralized with saturatedaqueous NaHCO₃ solution to pH 2-3. The aqueous layer was extracted withEtOAc (2×25 mL), dried (Na₂SO₄), and concentrated. The obtained residuewas purified by flash chromatography on silica gel (50% EtOAc-hexanes)to afford4-chloro-N-[5-chloro-2-(7-chloro-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(40 mg) as a white solid in 56% yield. MS m/z: 537 (M+H), 559 (M+Na).

Example 84:4-Chloro-N-[5-chloro-2-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(250 mg, 0.50 mmol) in THF (3.0 mL) under nitrogen atmosphere at 0° C.was added isopropylmagnesium chloride (0.60 mL, 1.2 mmol, 2M in THF).The mixture was then stirred for 30 min at 0° C. and 2-formyl-benzoicacid methyl ester (164 mg, 1.0 mmol) was added. The aqueous layer wasstirred at room temperature overnight, quenched with saturated aqueousammonium chloride, and followed by sodium bicarbonate to pH ˜6. Themixture was extracted with ethyl acetate, dried, and concentrated toprovide4-chloro-N-[5-chloro-2-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.The crude residue was used directly in the next step.

Example 85:4-Chloro-N-[5-chloro-2-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A solution of4-chloro-N-[5-chloro-2-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidein 3 mL HCl (4M in dioxane) and 1 mL water was refluxed for 2 h. Aftercooling to room temperature, the mixture was concentrated and theresidue was purified via preparative TLC (50% EtOAc in hexane) toprovide 11 mg of4-chloro-N-[5-chloro-2-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamideas an off white solid. MS m/z 503.3 (M+H).

Example 86:N-[2-(2-Amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred suspension of Fe (376 mg, 6.73 mmol) in glacial AcOH (10mL) at 80° C. was added a solution4-chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(700 mg, 1.34 mmol) in AcOH (5 mL) over 15 min. After complete addition,the mixture was stirred for 2 h and the progress of the reaction wasfollowed by LCMS. Upon consumption of reactants, the reaction mixturewas cooled to room temperature, diluted with EtOAc, and filtered througha pad of Celite. The filtrate was concentrated under reduced pressureand residue was partitioned with aqueous NaHCO₃ and EtOAc. The organicportion was separated and the aqueous portion was extracted with EtOAc.The combined extracts were dried (Na₂SO₄), filtered, and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel to provideN-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.MS m/z: 556.0 (M+Na).

Example 87:4-Chloro-N-{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred suspension ofN-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidein pyridine (1 mL) was added methanesulfonyl chloride (26 mg, 0.226mmol). After 2 h the reaction mixture was poured into 1M HCl and theaqueous portions were subsequently extracted with EtOAc. The combinedextracts were dried and concentrated under reduced pressure. Theresulting residue was dissolved in THF (5 mL), treated with TBAF (1M inTHF, 200

L, 0.200 mmol), and then stirred at room temperature for 3-4 h. Thereaction mixture was subsequently poured into 1M HCl and the aqueouslayer was extracted with EtOAc. The combined organic extracts were dried(Na₂SO₄), filtered, and concentrated under reduced pressure to provide4-chloro-N-[5-chloro-2-(2-methanesulfonylamino-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.MS m/z: 634.0 (M+Na).

A mixture of this crude product, K₂CO₃ (31 mg, 0.226 mmol), andiodomethane (15

L, 0.226 mmol) in anhydrous DMF (1 mL) were stirred at 50° C. overnight.The resulting mixture was poured into water and extracted with EtOAc.The extracts were concentrated to dryness under reduced pressure toprovide4-chloro-N-{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.MS m/z: 648.3 (M+Na).

Example 88:4-Chloro-N-{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

A mixture4-chloro-N-{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(30 mg crude) in 4M HCl in dioxane (12 mL) and water (4 mL) were heatedat 100° C. for 18 h. The reaction mixture was concentrated to drynessunder reduced pressure and subsequently neutralized aqueous NaHCO₃ to pHto 5-6. The aqueous layer was extracted with EtOAc, the combinedextracts were dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified by preparative HPLC (20→80% gradientof MeCN-water) to provide4-chloro-N-{5-chloro-2-[2-(methanesulfonyl-methyl-amino)-benzoyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamideas a solid. MS m/z: 582.0 (M+H).

Example 89: 5-Chloro-2-(2-fluoro-6-methoxy-phenoxy)-pyridin-3-ylamine

To a stirred solution of 2-bromo-5-chloro-3-nitropyridine (2.37 g, 10mmol) was dissolved in 40 mL DMF was added of 2-methoxyl-6-fluorophenol(1.7 g 11.9 mmol) was added into the solution followed by potassiumcarbonate (2.76, 20 mmol). The mixture was stirred at room temperaturefor 5 h, then poured into ice water (200 mL). The precipitate wasfiltered and dried under high vacuum to provide5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-3-nitro-pyridine.

AcOH (30 mL) and iron powder (5 g) were charged into a round bottomflask equipped with a magnetic stirring bar and warmed to 80° C. Asolution of crude5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-3-nitro-pyridine in AcOH wasadded slowly into the mixture, keeping the temperature under 85° C. Thereaction mixture was then cooled to room temperature, diluted withEtOAc, and filtered through a pad of Celite. The filtrate wasconcentrated under reduced pressure and the residue was partitionedbetween NaHCO₃ and EtOAc. The organic portion was separated and theaqueous portion was extracted with EtOAc. The combined extracts weredried (Na₂SO₄), filtered, and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel toprovide 5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-pyridin-3-ylamine (3.56g) as a colorless powder.

Example 90: General Procedure C: Synthesis of3-Amino-5-chloro-pyridin-2-yl Aryl Ketones

Step 1

To a stirred solution of 5-chloro-2-iodo-3-nitro-pyridine (2.85 g, 10.01mmol) in anhydrous THF (20 mL) at −78° C. was added 2Mphenylmagnesiumchloride in THF (5.22 mL, 10.5 mmol). The reactionmixture stirred at the same temperature for 30 min and the appropriatealdehyde (15 mmol) was added in one portion (either via syringe ifliquid or as solid). and the progress of the reaction was followed byLCMS. The reaction mixture was warmed to room temperature and stirredseveral hours (5-18 h). It was then quenched with saturated aqueousNH₄Cl (10 mL), and the aqueous layer was extracted with EtOAc. Thecombined extracts were washed with aqueous NaHCO₃ and brine, dried(Na₂SO₄), filtered, and concentrated under reduced pressure to affordthe desired benzylic alcohol which was directly in the followingreaction without further purification.

Step 2

A mixture of crude secondary alcohol and Dess-Martin periodinane (6.4 g,15 mmol) in CH₂Cl₂ (30 mL) at room temperature was stirred for 5-10 h. Amixture of 10% aqueous Na₂S₂O₃ (20 mL) and saturated aqueous NaHCO₃ (20mL) was then added and the biphasic mixture vigorously stirred for 30min. The phases were then separated and the aqueous portion extractedwith CH₂Cl₂. The combined organic extracts were washed with saturatedaqueous NaHCO₃ and brine, dried (Na₂SO₄), and filtered. The filtrate wasconcentrated under reduced pressure and the residue purified by flashcolumn chromatography over silica gel to provide the corresponding nitroketone.

Step 3

To a stirred suspension of Fe (4-5 equiv.) in glacial AcOH at 80° C. wasadded a solution of nitropyridyl ketone (1 equiv.) in AcOH (5 mL) over15 minutes. After complete addition, the mixture was stirred at the sametemperature for 1-2 h. The reaction mixture was cooled to roomtemperature, and diluted with EtOAc and filtered through a pad ofCelite. The filtrate was concentrated under reduced pressure and residuewas partitioned between NaHCO₃ and EtOAc. The organic layer wasseparated and the aqueous portion was extracted with EtOAc. The combinedextracts were dried (Na₂SO₄), filtered, and concentrated under reducedpressure. The residue was purified by flash column chromatography onsilica gel to provide the corresponding aniline.

Example 91: (3-Amino-5-chloro-pyridin-2-yl)-(2-chloro-phenyl)-methanone

(3-Amino-5-chloro-pyridin-2-yl)-(2-chloro-phenyl)-methanone was preparedfrom 2-chlorobenzaldehyde and 5-chloro-2-iodo-3-nitro-pyridine in threesteps according to the general procedure for synthesis of3-Amino-5-chloro-pyridin-2-yl aryl ketones. MS m/z: 267.0 (M+H).

Example 92: (3-Amino-5-chloro-pyridin-2-yl)-(2-methoxy-phenyl)-methanone

(3-Amino-5-chloro-pyridin-2-yl)-(2-methoxy-phenyl)-methanone wasprepared from 2-methoxybenzaldehyde and 5-chloro-2-iodo-3-nitro-pyridinein three steps according to the General Procedure C. MS m/z: 263.1(M+H).

Example 93:(3-Amino-5-chloro-pyridin-2-yl)-(2-fluoro-6-methoxy-phenyl)-methanone

(3-Amino-5-chloro-pyridin-2-yl)-(2-fluoro-6-methoxy-phenyl)-methanonewas prepared from 2-fluoro-6-methoxybenzaldehyde and5-chloro-2-iodo-3-nitro-pyridine in three steps according to the GeneralProcedure C. MS m/z: 281.0 (M+Na).

Example 94:3,4-Dichloro-N-[5-chloro-2-(2-chloro-benzoyl)-pyridin-3-yl]-benzenesulfonamide

A mixture of (3-amino-5-chloro-pyridin-2-yl)-(2-chloro-phenyl)-methanone(26.8 mg, 0.10 mmol) and 3,4-dichloro-benzenesulfonyl chloride (24.5 mg,0.10 mmol) in anhydrous pyridine (1 mL) were stirred overnight at 60° C.Reaction mixture was concentrated and the residue was treated with 1MNaOH (5 mL) and THF (5 mL) to hydrolyze bis-sulfonamide. The resultantsolution was neutralized to pH 6 and the aqueous layer was extractedwith EtOAc. The combined organic extracts were washed with brine, dried(Na₂SO₄) and concentrated. The was purified by preparative HPLC (20→90%gradient of MeCN-water) and pure product fractions were lyophilized toprovide3,4-dichloro-N-[5-chloro-2-(2-chloro-benzoyl)-pyridin-3-yl]-benzenesulfonamideas a solid. MS m/z: 498.0 (M+Na).

Example 95:3,4-Dichloro-N-[5-chloro-2-(2-methoxy-benzoyl)-pyridin-3-yl]-benzenesulfonamide

Following the procedure in example 94,3,4-dichloro-N-[5-chloro-2-(2-methoxy-benzoyl)-pyridin-3-yl]-benzenesulfonamidewas synthesized from(3-amino-5-chloro-pyridin-2-yl)-(2-methoxy-phenyl)-methanone (54 mg,0.206 mmol) and 3,4-dichloro-benzenesulfonyl chloride (101 mg, 0.412mmol). MS m/z: 471.0 (M+H).

Example 96:3,4-Dichloro-N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-benzenesulfonamide

Following the procedure in example 94,3,4-dichloro-N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-benzenesulfonamidewas synthesized from(3-amino-5-chloro-pyridin-2-yl)-(2-fluoro-6-methoxy-phenyl)-methanone(54 mg, 0.192 mmol) and 3,4-dichloro-benzenesulfonyl chloride (87 mg,0.368 mmol). MS m/z: 510.9 (M+Na).

Example 97:4-Chloro-N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-3-methyl-benzenesulfonamide

Following the procedure in example 94,4-chloro-N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-3-methyl-benzenesulfonamidewas synthesized from(3-amino-5-chloro-pyridin-2-yl)-(2-fluoro-6-methoxy-phenyl)-methanone(56 mg, 0.20 mmol) and 4-Chloro-3-methyl-benzenesulfonyl chloride (87mg, 0.368 mmol). MS m/z: 491.0 (M+Na).

Example 98:4-Chloro-N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-3-methyl-benzenesulfonamide

Following the procedure in example 94,4-chloro-N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-3-methyl-benzenesulfonamidewas synthesized from(3-amino-5-chloro-pyridin-2-yl)-(2-fluoro-6-methoxy-phenyl)-methanone(66 mg, 0.20 mmol) and 4-bromo-3-methyl-benzenesulfonyl chloride (120mg, 0.448 mmol). MS m/z: 491.0 (M+Na).

Example 99:2-Chloro-N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-benzenesulfonamide

Following the procedure in example 94,2-chloro-N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-benzenesulfonamidewas synthesized from(3-amino-5-chloro-pyridin-2-yl)-(2-fluoro-6-methoxy-phenyl)-methanone(50 mg, 0.178 mmol) and 2-chloro-benzenesulfonyl chloride (83 mg, 0.392mmol). MS m/z: 455.0 (M+H).

Example 100:4-Chloro-N-[5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Following the procedure in example 94,4-chloro-N-[5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamidewas synthesized from5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-pyridin-3-ylamine (100 mg),4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (100 mg). MS m/z:511.1 (M+H).

Example 101:5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicAcid

To a solution of4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(590 mg, 1.33 mmol) in tert-butanol (26 mL) was added isobutylene (5mL), sodium chlorite (751 mg, 6.66 mmol) sodium dihydrogen phosphate(919 mg, 6.66 mmol) and water (26 mL). After the solution was stirred atroom temperature for 3 h, EtOAc (10 mL) was added and the layers wereseparated. The organic layer was washed with saturated sodiumbicarbonate (2×10 mL) and brine (1×10 mL), dried over magnesium sulfate,filtered, and concentrated in vacuo to yield5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid as a white solid.

Example 102:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid isopropyl-phenyl-amide

To a magnetically stirred solution of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid (229 mg, 0.50 mmol) in anhydrous methylene chloride (5 mL) wasadded oxalyl chloride (1.0 mL) at room temperature. The reaction washeated at reflux for 2 h, then concentrated to dryness. The residue wasdissolved in methylene chloride (4 mL) and this solution was addeddropwise to a magnetically stirred solution of triethylamine (1.0 mL)and N-isopropylaniline (135 mg, 1.00 mmol) in methylene chloride (2 mL).The reaction mixture was stirred 1 h (the reaction was monitored byLCMS), then quenched with saturated aqueous NH₄Cl (50 mL), and theaqueous layer extracted with EtOAc (3×75 mL). The combined extracts werewashed with 0.5M HCl (50 mL), washed with water (50 mL), dried (MgSO₄),filtered, and concentrated. The residue was purified by chromatographyon silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0)to afford pure5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid N-isopropyl-N-phenylamide. MS m/z 576.0 (M+H); 544.0 (M+H−MeOH).

The intermediate MOM derivative (180 mg, 0.313 mmol) was magneticallystirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL) at 85° C. (oilbath) for 7 h. Upon consumption of the reactant, the reaction mixturewas concentrated, the residue neutralized (pH 7) with aqueous sodiumbicarbonate, and the aqueous layer extracted with EtOAc (3×80 mL). Thecombined organic extracts were dried (MgSO₄), filtered, andchromatographed on silica gel using ethyl acetate-hexane gradient (0:100to 50:50) to provide5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid isopropyl-phenyl-amide. MS m/z 532.0 (M+H).

Example 103:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfinylamino)-pyridine-2-carboxylicAcid Phenylamide

To a magnetically stirred solution of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid (229 mg, 0.50 mmol) in anhydrous methylene chloride (5 mL) wasadded oxalyl chloride (0.5 mL) at room temperature. The reaction washeated at reflux for 1 h, then concentrated to dryness. The residue wasdissolved in methylene chloride (4 mL) and this solution was addeddropwise to a magnetically stirred solution of triethylamine (1.0 mL)and aniline (93 mg, 1.00 mmol) in methylene chloride (2 mL). Thereaction mixture was stirred 1 h (the reaction was monitored by LCMS),quenched with saturated aqueous NH₄Cl (50 mL), and the aqueous layer wasextracted with EtOAc (3×75 mL). The combined extracts were washed with0.5M HCl (50 mL) and water (50 mL), dried (MgSO₄), filtered, andconcentrated. The residue was purified by chromatography on silica gelusing a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid phenylamide. MS m/z 556.1 (M+Na); 502.1 (M+H−MeOH).

5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid phenylamide (120 mg, 0.224 mmol) was magnetically stirred in water(1.0 mL) and 4N HCl in dioxane (2.5 mL) at 85° C. (oil bath) for 4 h.Upon consumption of the reactant, the reaction mixture was concentrated,the residue neutralized (pH 7) with aqueous sodium bicarbonate, and theaqueous layer was extracted with EtOAc (3×80 mL). The combined organicextracts were dried (MgSO₄), filtered, and chromatographed on silica gelusing ethyl acetate-hexane gradient (0:100 to 50:50) to provide purefinal product. MS m/z 490.0 (M+H).

Example 104:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid N-methyl-N-phenylamide

To a magnetically stirred solution of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid (458 mg, 1.00 mmol) in anhydrous methylene chloride (5 mL) wasadded oxalyl chloride (1.0 mL) at room temperature. The reaction washeated at reflux for 2 h, then concentrated to dryness. The residue wasdissolved in methylene chloride (4 mL) and this solution was addeddropwise to a magnetically stirred solution of triethylamine (1.0 mL)and N-methylaniline (108 mg, 1.00 mmol) in methylene chloride (2 mL).The reaction mixture was stirred 1 h (the reaction was monitored byLCMS), quenched with saturated aqueous NH₄Cl (50 mL), and the aqueouslayer was extracted with EtOAc (3×75 mL). The combined extracts werewashed with 0.5M HCl (50 mL), washed with water (50 mL), dried (MgSO₄),filtered and concentrated. The residue was purified by chromatography onsilica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) toafford pure5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid N-methyl-N-phenylamide. MS m/z: 548.2 (M+H), 526.0 (M+H−MeOH).

5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid N-methyl-N-phenylamide (132 mg, 0.24 mmol) was magnetically stirredin water (1.0 mL) and 4N HCl in dioxane (2.5 mL) and heated at 85° C.(oil bath) for 7 h. LCMS indicated complete reaction; the reaction wasconcentrated and the residue was neutralized (pH 7) with aqueous sodiumbicarbonate and the aqueous layer was extracted with EtOAc (3×80 mL).The extracts were dried (MgSO₄), filtered, and chromatographed on silicagel using ethyl acetate-hexane gradient (0:100 to 50:50) to provide5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid N-methyl-N-phenylamide. MS m/z: 504.1 (M+H).

Example 105:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid N-methyl-N-(4-fluorophenyl)amide

To a magnetically stirred solution of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid (458 mg, 1.00 mmol) in anhydrous methylene chloride (5 mL) wasadded oxalyl chloride (1.0 mL) at room temperature. The reaction washeated at reflux for 1 h then was concentrated to dryness. The residuewas dissolved in methylene chloride (4 mL) and this solution was addeddropwise to a magnetically stirred solution of triethylamine (1.0 mL)and N-methyl-N-(4-fluorophenyl)aniline (0.50 mL, 3.5 mmol) in methylenechloride (2 mL). The reaction mixture was stirred 1 h (the reaction wasmonitored by LCMS) then quenched with saturated aqueous NH₄Cl (50 mL),and extracted with EtOAc (3×75 mL). The combined extracts were washedwith 0.5M HCl (50 mL), washed with water (50 mL), dried (MgSO₄),filtered and concentrated. The residue was purified by chromatography onsilica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) toafford pure5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid N-methyl-N-(4-fluorophenyl)amide. MS m/z 570.1 (M+Na); 526.0(M+H−MeOH).

5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid N-methyl-N-(4-fluorophenyl)amide (141 mg, 0.258 mmol) wasmagnetically stirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL)and heated at 85° C. (oil bath) for 7 h. LCMS indicated completereaction; the reaction was concentrated and the residue was neutralized(pH 7) with aqueous sodium bicarbonate and extracted with EtOAc (3×80mL). The extracts were dried (MgSO₄), filtered, and chromatographed onsilica gel using ethyl acetate-hexane gradient (0:100 to 50:50) toprovide5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid N-methyl-N-(4-fluorophenyl)amide. MS m/z 522.1 (M+H).

Example 106:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid 2-isopropylaminopyridin-2-yl Amide

To a magnetically stirred solution of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid (229 mg, 0.50 mmol) in anhydrous methylene chloride (5 mL) wasadded oxalyl chloride (0.5 mL) at room temperature. The reaction washeated at reflux for 1 h then was concentrated to dryness. The residuewas dissolved in methylene chloride (4 mL) and this solution was addeddropwise to a magnetically stirred solution of triethylamine (1.0 mL)and 2-(isopropylamino)pyridine (136 mg, 1.00 mmol) in methylene chloride(2 mL). The reaction mixture was stirred 1 h (the reaction was monitoredby LCMS) then quenched with saturated aqueous NH₄Cl (50 mL), andextracted with EtOAc (3×75 mL). The combined extracts were washed with0.5M HCl (50 mL), washed with water (50 mL), dried (MgSO₄), filtered andconcentrated. The residue was purified by chromatography on silica gelusing a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid 2-(isopropylamino)pyridylamide. MS m/z 577.1 (M+H).

5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid 2-(isopropylamino)pyridylamide (120 mg, 0.208 mmol) wasmagnetically stirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL)and heated at 85° C. (oil bath) for 9 h. LCMS indicated completereaction; the reaction was concentrated and the residue was neutralized(pH 7) with aqueous sodium bicarbonate and extracted with EtOAc (3×80mL). The extracts were dried (MgSO₄), filtered, and chromatographed onsilica gel using ethyl acetate-hexane gradient (0:100 to 50:50) toprovide5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid 2-isopropylaminopyridin-2-yl amide. MS m/z: 533.1 (M+H).

Example 107:4-Chloro-N-[5-chloro-2-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a mixture of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid (112 mg, 0.244 mmol), 100 mg (0.70 mmol) of3,4-dihydro-2H-benzo[1,4]oxazine, and 0.174 mL (1.0 mmol) of DIEA inCH₂Cl₂ (2.5 mL) was added 0.19 mL 1-propanephosphonic acid cyclicanhydride (50% in ethyl acetate). After 3 h the reaction mixture wasdirectly purified via flash column (50% EtOAc in hexane) to afford 79 mgof4-chloro-N-[5-chloro-2-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideas a white powder. MS m/z: 576.38 (M+H).

Example 108:4-Chloro-N-[5-chloro-2-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A solution of4-chloro-N-[5-chloro-2-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(50 mg) in 3 mL HCl (4M in dioxane) and water (1 mL) was refluxed for 2h. Upon cooling to room temperature, the mixture was concentrated andthe residue was purified via preparative TLC (50% EtOAc in hexane) toafford4-chloro-N-[5-chloro-2-(2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(27.0 mg) as an off white solid. MS m/z: 532.2 (M+H).

Example 109:4-Chloro-N-[5-chloro-2-(3-methyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a mixture of 112 mg (0.244 mmol) of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid, 70 mg (0.70 mmol) of 2-methylmorpholine and 0.174 mL (1.0 mmol) ofDIEA in CH₂Cl₂ (2.5 mL) was added 0.19 mL 1-propanephosphonic acidcyclic anhydride (50% in ethyl acetate). After 3 h the reaction mixturewas directly purified via flash column (50% EtOAc in hexane) to afford67 mg of4-chloro-N-[5-chloro-2-(3-methyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideas a white powder. MS m/z: 542.36 (M+H).

Example 110:4-Chloro-N-[5-chloro-2-(3-methyl-morpholine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A solution of4-chloro-N-[5-chloro-2-(3-methyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(40 mg) in 3 mL HCl (4M in dioxane) and water (1 mL) was refluxed for 2h. Upon Cooling to room temperature, the mixture was concentrated andthe residue was purified via preparative TLC (50% EtOAc in hexane) toafford 21 mg of4-chloro-N-[5-chloro-2-(3-methyl-morpholine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamideas an off white solid. MS m/z: 498.0 (M+H).

Example 111:5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonylChloride

To a solution of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid (450 mg, 1.0 mmol) in 3.0 mL CH₂Cl₂ and DMF (0.02 mL) was addedoxalyl chloride (0.110 mL). The mixture was stirred for 2 h andconcentrated to dryness provide5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonylchloride.

Example 112:4-Chloro-N-[5-chloro-2-(3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

A mixture of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonylchloride (50 mg, 0.11 mmol), 3-sethyl-3,4-dihydro-2H-benzo[1,4]oxazine(60 mg, 0.40 mmol) and di-isopropylethylamine (DIEA, 0.07 mL, 0.40 mmol)in CH₂CL₂ (1.5 mL) was stirred at room temperature overnight. Themixture was concentrated to provide4-chloro-N-[5-chloro-2-(3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide,which was directly used in the next step without any purification.

Example 113:4-Chloro-N-[5-chloro-2-(2,6-dimethyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

A mixture of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonylchloride (50 mg, 0.11 mmol), cis-2,6-dimethylmorpholine (50 mg, 0.40mmol) and di-isopropylethylamine (DIEA, 0.07 mL, 0.40 mmol) in CH₂Cl₂(1.5 mL) was stirred at room temperature overnight. The mixture wasconcentrated to provide4-chloro-N-[5-chloro-2-(cis-2,6-dimethyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide,which was directly used in the next step without any purification.

Example 114:4-Chloro-N-[5-chloro-2-(3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A solution of crude4-chloro-N-[5-chloro-2-(3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidein 3 mL HCl (4M in dioxane) and water (1 mL) was refluxed for 2 h. Uponcooling to room temperature, the mixture was concentrated and theresidue was purified via preparative TLC (50% EtOAc in hexane) to afford11 mg of4-chloro-N-[5-chloro-2-(3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamideas an off white solid. MS m/z: 546.1 (M+H).

Example 115:4-Chloro-N-[5-chloro-2-(2,6-dimethyl-morpholine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A solution of crude4-chloro-N-[5-chloro-2-(2,6-dimethyl-morpholine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidein 3 mL HCl (4M in dioxane) and water (1 mL) was refluxed for 2 h. Uponcooling to room temperature, the mixture was concentrated and theresidue was purified via preparative TLC (50% EtOAc in hexane) to afford28 mg of4-chloro-N-[5-chloro-2-(2,6-dimethyl-morpholine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamideas an off white solid. MS m/z: 512.0 (M+H).

Example 116:5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic Acid

Step 1

A dry 250 mL flask was charged with 2-bromo-5-chloro-3-nitropyridine (24g, 10 mmol), CuCN (19 g, 20 mmol) and DMF (100 mL). The resultantmixture was stirred at 110° C. for 2 h and then concentrated underreduced pressure. Water (100 mL) was added and the aqueous layer wasextracted with EtOAc (250 mL×3). The combined organic layer was washedwith brine, dried (MgSO₄), and evaporated in vacuo to afford a lightyellow solid (15 g) which was used directly for the next step.

Step 2

A 250 mL round-bottom flask was charged with the iron powder (15.6 g,0.3 mol), AcOH (80 mL) and heated to 80° C. (oil bath) under N₂. To thismixture, was added a solution of nitrocyanopyridine (10 g, 0.055 mmol)in AcOH (80 mL) via addition funnel and stirred at 80° C. for anadditional 30 min after the addition. The reaction was subsequentlycooled to room temperature, diluted with EtOAc, filtered through a padof Celite and concentrated under reduced pressure. The residue wasdissolved in EtOAc and washed with 3N NaOH and brine, dried over MgSO₄,and concentrated under reduced pressure and to afford the crude3-amino-2-cyano-5-chloropyridine along with the 2-amide (7.7 g) whichwas used directly for the next step: MS 154.0 (M+H).

Step 3

A 500 mL round-bottom flask was charged with the above3-amino-2-cyano-5-chloropyridine (7.7 g, 50 mmol),4-Cl-3-trifluoromethyl-benzenesulfonyl chloride (28 g, 100 mmol), andpyridine (50 mL). The resultant solution was heated to 70° C. andstirred for 5 h. The pyridine was removed in vacuo and EtOH (80%, 260mL) was added, followed by NaOH (30 g, 0.75 mol). The mixture was heatedat reflux for 12 h. The solvent was subsequently removed in vacuo andice (100 g) was added and the pH adjusted to 2-3 with conc HCl. Theresultant aqueous solution was extracted with EtOAc, washed with brine,dried over MgSO₄, and concentrated under reduced pressure. The resultantlight yellow solid was further crystallized from EtOAc/hexane (1:1) toafford5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acidas white needles (10 g, 44% overall): ¹H NMR (400 MHz, CDCl₃) δ 10.80(s, 1H), 8.23 (m, 3H), 8.00 (d, 1H), 7.63 (d, 1H); MS (ES) 415.0 (M+H).

Example 117: General Procedure D: Synthesis of5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinicAmides

A 10 mL scintillation vial was charged with5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(1 equiv), amine (2-3 equiv.), coupling agent [HATU, BOP or T3P, 1.1-1.3equiv), and base [DIEA (3-5 equiv.) or Et₃N (1-3 equiv.)] in anhydrousDMF (or CH₂Cl₂). The resultant solution was stirred at room temperature(or 70° C.) for several hours until the starting material was consumed.The reaction mixture was diluted with MeCN (1-2 mL) and purified bypreparative HPLC (20→90% gradient of MeCN-water) and pure productfractions were lyophilized to provide pure product as a solid.Non-commercial amines were prepared according to procedures available inliterature.

Example 118:4-chloro-N-(5-chloro-2-(1,2,3-4-tetrahydro-1,5-naphyridine-1-carbonyl-pyridine-3-yl)-3-(trifluoromethyl)benzenefulfonamide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(164 mg, 0.4 mmol), 1,2,3,4-tetrahydro-1,5-napthyridine [(70 mg, 0.56mmol), 1,2,3,4-tetrahydro-1,5-napthyridine prepared freshly from1,5-napthyridine via hydrogenation over Pt₂O], HATU (200 mg, 0.5 mmol),DIEA (260 mg, 2 mmol) were reacted according to the procedure D toprovide the title compound. HPLC purification (20→90% gradient ofMeCN-water) provided4-chloro-N-(5-chloro-2-(1,2,3-4-tetrahydro-1,5-naphyridine-1-carbonyl-pyridine-3-yl)-3-(trifluoromethyl)benzenefulfonamide:¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, 1H), 8.18 (m, 2H), 8.09 (d, 1H), 8.00(m, 2H), 7.69 (d, 1H), 7.52 (m, 1H), 3.92 (m, 2H), 3.35 (t, 2H), 2.11(m, 2H); MS m/z: 531.0 (M+H).

Example 119:5-Chloro-3(4-chloro-3-(trifluoromethyl)phenysulfonamido)-N-ethyl-(thiazol-2-yl)picolinamide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(120 mg, 0.3 mmol), 2-ethylaminothiazole [(50 mg, 0.4 mmol)2-Ethylaminothiazole was prepared freshly from 2-aminothiazole andacetylaldehyde via standard reductive amination condition using NaCNBH₃as the reducing agent], HATU (190 mg, 0.5 mmol), DIEA (130 mg, 1 mmol)were reacted according to the procedure D to provide the title compound.HPLC purification (20→90% gradient of MeCN-water) provided5-Chloro-3(4-chloro-3-(trifluoromethyl)phenysulfonamido)-N-ethyl-(thiazol-2-yl)picolinamide:¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.82(d, 1H), 7.61 (s, 1H), 7.46 (d, 1H), 7.20 (s, 1H), 6.0 (s, 2H), 4.02 (q,2H), 1.25 (t, 3H); MS m/z 525.0 (M+H).

Example 120:4-Chloro-N-[5-chloro-2-(3,4-dihydro-2H-[1,8]naphthyridine-1-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(208 mg, 0.50 mmol), 1,2,3,4-tetrahydro-[1,8]naphthyridine [(135 mg, 1.0mmol) 1,2,3,4-tetrahydro-[1,8]naphthyridine was prepared freshly from1,8-napthyridine via hydrogenation over Pt₂O], BOP (486 mg, 1.1 mmol),DIEA (185 mg, 1.4 mmol) were reacted according to the procedure D toprovide the title compound. HPLC purification (20→90% gradient ofMeCN-water) provided4-chloro-N-[5-chloro-2-(3,4-dihydro-2H-[1,8]naphthyridine-1-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide:MS m/z: 531.0 (M+H).

Example 121:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid methyl-m-tolyl-amide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(50 mg, 0.12 mmol), methyl-m-tolyl-amine (44 mg, 0.36 mmol), BOP (69 mg,0.36 mmol), DIEA (130

L, 0.72 mmol) were reacted according to the procedure D to provide thetitle compound. HPLC purification (20→90% gradient of MeCN-water)provided5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methyl-m-tolyl-amide: MS m/z: (M+H) 518.1.

Example 122:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid (3-chloro-phenyl)-methyl-amide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(50 mg, 0.12 mmol), (3-chloro-phenyl)-methyl-amine (50 mg, 0.36 mmol),BOP (69 mg, 0.36 mmol), DIEA (130

L, 0.72 mmol) were reacted according to the procedure D to provide thetitle compound. HPLC purification (20→90% gradient of MeCN-water)provided5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (3-chloro-phenyl)-methyl-amide: MS m/z: (M+H) 537.9.

Example 123:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid (3-fluoro-phenyl)-methyl-amide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(50 mg, 0.12 mmol), (3-fluoro-phenyl)-methyl-amine (45 mg, 0.36 mmol),BOP (69 mg, 0.36 mmol), DIEA (130

L, 0.72 mmol) were were reacted according to the procedure D to providethe title compound. HPLC purification (20→90% gradient of MeCN-water)provided5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (3-fluoro-phenyl)-methyl-amide: MS m/z: (M+H) 521.9.

Example 124:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid methyl-pyridin-2-yl-amide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(75 mg, 0.18 mmol), methyl-pyridin-2-yl-amine (60 mg, 0.54 mmol), BOP(103 mg, 0.234 mmol), DIEA (193

L, 1.08 mmol) were reacted according to the procedure D to provide thetitle compound. HPLC purification (20→90% gradient of MeCN-water)provided5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methyl-pyridin-2-yl-amide: MS m/z: (M+H) 505.1.

Example 125:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid (2,4-difluoro-phenyl)-methyl-amide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(100 mg, 0.24 mmol), (2,4-difluoro-phenyl)-methyl-amine (103 mg, 0.72mmol), BOP (137 mg, 0.31 mmol), DIEA (265

L, 1.44 mmol) were reacted according to the procedure D to provide thetitle compound. HPLC purification (20→90% gradient of MeCN-water)provided5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (2,4-difluoro-phenyl)-methyl-amide: MS m/z: (M+H) 541.0.

Example 126:2-{[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-methyl-amino}-benzoicAcid Methyl Ester

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(100 mg, 0.24 mmol), 2-methylamino-benzoic acid methyl ester (119 mg,0.722 mmol), BOP (137 mg, 0.312 mmol), DIEA (265

L, 1.08 mmol) were reacted according to the procedure D to provide thetitle compound. HPLC purification (20→90% gradient of MeCN-water)provided2-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-methyl-amino}-benzoicacid methyl ester: MS m/z: (M+H) 562.1.

Example 127:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid methyl-o-tolyl-amide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(50 mg, 0.12 mmol), methyl-o-tolyl-amine (44 mg, 0.36 mmol), BOP (69 mg,0.36 mmol), DIEA (130

L, 0.72 mmol) were reacted according to the procedure D to provide thetitle compound. HPLC purification (20→90% gradient of MeCN-water)provided5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methyl-o-tolyl-amide: MS m/z: (M+H) 518.0.

Example 128:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid (2-fluoro-phenyl)-methyl-amide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(50 mg, 0.12 mmol), (2-fluoro-phenyl)-methyl-amine (45 mg, 0.36 mmol),BOP (69 mg, 0.36 mmol), DIEA (130

L, 0.72 mmol) were reacted according to the procedure D to provide thetitle compound. HPLC purification (20→90% gradient of MeCN-water)provided5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (2-fluoro-phenyl)-methyl-amide: MS m/z: (M+H) 522.1.

Example 129:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid (2-chloro-phenyl)-methyl-amide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(50 mg, 0.12 mmol), (2-chloro-phenyl)-methyl-amine (50 mg, 0.36 mmol),BOP (69 mg, 0.36 mmol), DIEA (130

L, 0.72 mmol) were reacted according to the procedure D to provide thetitle compound. HPLC purification (20→90% gradient of MeCN-water)provided5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (2-chloro-phenyl)-methyl-amide: MS m/z: (M+H) 537.4.

Example 130:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid ethyl-pyridin-2-yl-amide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(150 mg, 0.36 mmol), ethyl-pyridin-2-yl-amine (131 mg, 1.08 mmol), BOP(207 mg, 0.47 mmol), DIEA (400

L, 2.16 mmol) were reacted according to the procedure D to provide thetitle compound. HPLC purification (20→90% gradient of MeCN-water)provided5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid ethyl-pyridin-2-yl-amide: MS m/z: (M+H) 519.0.

Example 131:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid methyl-(6-methyl-pyridin-2-yl)-amide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(100 mg, 0.24 mmol), methyl-(6-methyl-pyridin-2-yl)-amine (88 mg, 0.72mmol), BOP (137 mg, 0.31 mmol), DIEA (265

L, 1.44 mmol) were reacted according to the procedure D to provide thetitle compound. HPLC purification (20→90% gradient of MeCN-water)provided5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methyl-(6-methyl-pyridin-2-yl)-amide: MS m/z: 519.0 (M+H).

Example 132:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid methyl-(4-methyl-pyridin-2-yl)-amide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid(100 mg, 0.24 mmol), methyl-(4-methyl-pyridin-2-yl)-amine (88 mg, 0.72mmol), BOP (137 mg, 0.31 mmol) and DIEA (265

L, 1.44 mmol) were reacted according to the procedure D to provide thetitle compound. HPLC purification (20→90% gradient of MeCN-water)provided5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methyl-(4-methyl-pyridin-2-yl)-amide: MS m/z: 519.0 (M+H).

Example 133:4-Chloro-N-[5-chloro-2-(8-fluoro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

8-Fluoro-3,4-dihydro-2H-benzo[1,4]oxazine,5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinicacid, T3P, and Et₃N were reacted according to the procedure D to providethe title compound. HPLC purification provided4-chloro-N-[5-chloro-2-(8-fluoro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide.Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 2.986min. MS m/z 550.1 (M+H).

Example 134:4-Chloro-N-[5-chloro-2-(6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazine5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinicacid, T3P, and Et₃N were reacted according to the procedure D to providethe title compound. HPLC purification provided4-chloro-N-[5-chloro-2-(6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide.Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 3.180min MS m/z: 567.1 (M+H).

Example 135:4-Chloro-N-[5-chloro-2-(2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazine5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinicacid, T3P, and Et₃N were reacted according to the procedure D to providethe title compound. HPLC purification provided4-chloro-N-[5-chloro-2-(2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide;Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 2.871min; MS m/z 533.1 (M+H).

Example 136:4-Chloro-N-[5-chloro-2-(6-fluoro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

6-Fluoro-3,4-dihydro-2H-benzo[1,4]oxazine5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinicacid, T3P, and Et₃N were reacted according to the procedure D to providethe title compound. HPLC purification provided4-chloro-N-[5-chloro-2-(6-fluoro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide:Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 3.041min MS m/z: 550.1 (M+H).

Example 137:4-Chloro-N-[5-chloro-2-(6-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

6-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinicacid, T3P, and Et₃N were reacted according to the procedure D to providethe title compound. HPLC purification provided4-chloro-N-[5-chloro-2-(6-methyl-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide:Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 3.099min; MS m/z: 546.1 (M+H).

Example 138: General Procedure E: Synthesis of 4-chlorobenzooxazin

3-Chlorophenol (2.87 g, 20 mmol) was added into a magnetically stirredmixture of 50 mL saturated aqueous solution of sodium bicarbonate and 30mL tetrahydrofuran. Chloroacetylchloride (2.82 g, 25 mmol) was added andthe reaction mixture was stirred at room temperature for 2 h. Thereaction was heated to 80° C. and stirred an additional 18 h. Themixture was poured into water (200 mL) and the aqueous layer wasextracted with ethyl acetate (200 mL). The combined organic extractswere concentrated and dried under high vacuum.

The crude product was dissolved in tetrahydrofuran (30 mL) and stirredunder nitrogen. 10 mL lithium aluminum hydride solution in THF (2.4M, 24mmol) was slowly added to the solution. The resultant mixture wasstirred at room temperature for 2 h, quenched by adding saturatedaqueous solution of sodium bicarbonate (20 mL). The aqueous layer wasextracted with 50 mL chloroform twice and the combined organic extractswere concentrated under reduced pressure. The crude product was purifiedby flash chromatograph to yield 3.13 g of product as a colorless solid.

Example 139: 5-Chloro-thiophene-2-sulfonic Acid[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-amide

(3-Amino-5-chloro-pyridin-2-yl)-(2-fluoro-6-methoxy-phenyl)-m ethanone(50 mg, 0.178 mmol) and 5-chloro-thiophene-2-sulfonyl chloride (85 mg,0.392 mmol) were reacted according to the procedure described in example94. The crude product was purified by flash chromatography on silica gelusing Combi-flash and pure product fractions were dried under reducedpressure to provide 5-chloro-thiophene-2-sulfonic acid[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-amide. MS m/z:460.9 (M+H).

Example 140:4-Chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(280 mg, 0.566 mmol) in anhydrous THF (3 mL) was added 2Misopropylmagnesiumchloride in THF (700

L, 1.36 mmol) at 0° C. It was stirred at the same temperature for 20minutes and then DMF (174

L, 1.36 mmol) was added in dropwise and the progress of the reaction wasfollowed by LCMS. The reaction mixture was warmed to room temperatureand stirred for 6 h. It was then quenched with saturated aqueous NH₄Cl(2 mL), and extracted with EtOAc. The combined extracts were dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography to provide4-Chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideMass spectrum m/z: 443.0 (M+H).

Example 141:4-Chloro-N-{5-chloro-2-[hydroxy-(2-nitro-phenyl)-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution of 1-iodo-2-nitro-benzene (769 mg, 3.08 mmol) inanhydrous THF (3 mL) was added 2M phenylmagnesiumchloride in THF (1.62mL, 3.24 mmol) at −40° C. under an atmosphere of nitrogen. It wasstirred at the same temperature for 15 minutes and then4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(1.04 g, 2.36 mmol) was added in one portion and the progress of thereaction was followed by LCMS. The reaction mixture was warmed to roomtemperature and stirred for 3 h. It was then quenched with saturatedaqueous NH₄Cl (2 mL), and extracted with EtOAc. The combined extractswere dried (Na₂SO₄), filtered and concentrated under reduced pressure toprovide crude4-chloro-N-{5-chloro-2-[hydroxy-(2-nitro-phenyl)-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide,which was used in the following step without any purification. Massspectrum m/z: 566.3 (M+H).

Example 142:4-Chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-{5-chloro-2-[hydroxy-(2-nitro-phenyl)-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(˜1.0 g) and Dess-Martin periodinane (1.50 g, 3.54 mmol) in CH₂Cl₂ (20mL) at room temperature was stirred for 2-4 h. A mixture of 10% aqueousNa₂S₂O₃ (10 mL) and saturated aqueous NaHCO₃ (10 mL) was then added andthe biphasic mixture vigorously stirred for 30 min. The phases were thenseparated and the aqueous portion extracted with CH₂Cl₂. The combinedorganic extracts were washed with saturated aqueous NaHCO₃, then brine,dried (Na₂SO₄) and filtered. The filtrate was concentrated under reducedpressure and the residue purified by flash column chromatography oversilica gel (EtOAc/hexanes, 1:4, then 2:3) to provide4-Chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.Mass spectrum m/z: 586.3 (M+Na).

Example 143:4-Chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture4-chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(580 g, 1.02 mmol) in 4M HCl in dioxane (15 mL), and water (5 mL) washeated at 100° C. for 8 h and then at room temperature for 10 h. Thereaction mixture was concentrated to dryness under reduced pressure andit was treated with aqueous NaHCO₃ to adjust pH to 5-6 and extractedwith EtOAc. The combined extracts were dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel to provide the desired product4-Chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide.¹H NMR (400 MHz, CDCl₃) δ 11.06 (s, 1H), 8.23 (d, J=2.4 Hz, 1H), 8.18(d, J=2.4 Hz, 1H), 8.14 (dd, J=8.0, 1.4 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H),8.00 (dd, J=8.4, 2.0 Hz, 1H), 7.80-7.77 (m, 1H), 7.70-7.66 (m, 2H), 7.45(dd, J=8.0, 1.6 Hz, 1H); Mass spectrum m/z: 520.2 (M+H).

Example 144:N-[2-(2-Amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide

To a stirred suspension of Fe (176 mg, 3.15 mmol) in glacial acetic acid(5 m L) was added a solution4-chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(410 mg, 0.788 mmol) in AcOH (5 mL) at 80° C. for 15 minutes. Aftercomplete addition the mixture was stirred at the same temperature for 30minutes and the progress of the reaction was followed by LCMS. Thereaction mixture was then cooled to room temperature and it was thendiluted with EtOAc and filtered through a pad of Celite. The filtratewas concentrated under reduced pressure and residue was portionedbetween NaHCO₃ and EtOAc. The organic portion was separated and theaqueous portion was extracted with EtOAc. The combined extracts weredried (Na₂SO₄), filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel toprovideN-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide.¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.12 (d,J=2.0 Hz, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.64-7.61 (m, 1H), 7.30-7.26 (m,2H), 7.03-7.00 (m, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.47-6.43 (m, 1H), 6.26(s, 2H); Mass spectrum m/z: 490.0 (M+H).

Example 145:4-Chloro-N-[5-chloro-2-(2-oxo-1,2-dihydro-quinazolin-4-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

To a stirred solution ofN-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide(48 mg, 0.097 mmol) in anhydrous THF (2 mL) and AcOH (400

L) was added TMSisocyanate (32

L, 0.22 mmol) and the resulting mixture was heated at 65° C. overnight.The crude reaction mixture was directly purified by HPLC to provide4-Chloro-N-[5-chloro-2-(2-oxo-1,2-dihydro-quinazolin-4-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide.¹H NMR (400 MHz, CDCl₃) δ 10.50 (br s, 1H), 8.58 (d, J=2.4 Hz, 1H), 8.19(d, J=2.4 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.92 (d, J=2.4 Hz, 1H),7.80-7.76 (m, 1H), 7.65 (dd, J=8.4, 2.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H),7.23-7.22 (m, 2H); Mass spectrum m/z: 515.0 (M+H).

Example 146:4-Chloro-N-[5-chloro-2-(2-methanesulfonylamino-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide(24 mg, 0.048 mmol) in anhydrous pyridine (1 mL) was added methanesulfonyl chloride (9 mg, 0.075 mmol). The resulting mixture was stirredat room temperature for 2 h was poured into 1M HCl and extracted withEtOAc. The extracts were concentrated under reduced pressure and theresidues was purified by flash column chromatography to trissulfonamideMass spectrum m/z: 515.0 (M+H). To this trisulfonamide (14 mg, 0.021mmol) in THF was added TBAF (1M in THF, 40

L, 0.04 mmol) and the resulting mixture was stirred overnight. Thereaction mixture was quenched with 1M HCl and extracted with EtOAc. Thecombined extracts were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (combi-flash) to provide4-Chloro-N-[5-chloro-2-(2-methanesulfonylamino-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide.¹H NMR (400 MHz, CDCl₃) δ 9.60 (br, 2H), 8.38 (d, J=2.0 Hz, 1H), 8.16(d, J=2.0 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.87 (dd, J=8.4, 2.4 Hz, 1H),7.72-7.70 (m, 1H), 7.62-7.57 (m, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.29 (dd,J=8.0, 2.4 Hz, 1H), 7.08-7.05 (m, 1H), 3.07 (s, 3H); Mass spectrum m/z:515.0 (M+H).

Example 147:4-Chloro-N-[5-chloro-2-(2-methylsulfanyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(8.26 g, 16.6 mmol) in anhydrous THF (50 mL) was added 2Misopropylmagnesiumchloride in THF (18.4 mL, 36.8 mmol) at −40° C. It wasthen warmed to 0° C. and stirred at the same temperature for 30 minutesand then N-Methoxy-N-methyl-2-methylsulfanyl-benzamide (10.5 g, 49.8mmol) was added in and the progress of the reaction was followed byLCMS. The reaction mixture was warmed to room temperature and stirredovernight (18 h). It was then quenched with saturated aqueous NH₄Cl (2mL), and extracted with EtOAc. The combined extracts were dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography to provide4-chloro-N-[5-chloro-2-(2-methylsulfanyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.Mass spectrum m/z: 486.9 (M+Na).

Example 148:4-Chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution of4-chloro-N-[5-chloro-2-(2-methylsulfanyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(10.0 g, 17.7 mmol) in CH₂Cl₂ (100 mL) was added m-CPBA (8.9 g, 75% bywt, 38.9 mmol) in one portion and the progress of the reaction wasmonitored by LCMS. After overnight stirring at room temperature, thereaction mixture was quenched with pyridine (10 mL) and reaction mixturewas stirred for 30 minutes. Then portioned between diethyl ether andwater, the aqueous portion was separated and the organic portion waswashed with NH₄Cl and NaHCO₃ respectively. The combined extracts weredried (Na₂SO₄), filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography to provide4-chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.Mass spectrum m/z: 497.4 (M+H).

Example 149:4-Chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture4-chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(9.6 g, 16.1 mmol) in 4M HCl in dioxane (60 mL), and water (15 mL) washeated at 100° C. for 20 h. The reaction mixture was concentrated todryness under reduced pressure and it was treated with aqueous NaHCO₃ toadjust pH to 5-6 and extracted with EtOAc. The combined extracts weredried (Na₂SO₄), filtered and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel toprovide the desired product. ¹H NMR (400 MHz, CDCl₃) δ 11.1 (S, 1H),8.22-8.14 (m, 2H), 8.00-7.97 (m, 1H), 7.72-7.65 (m, 3H), 7.33 (d, J=7.2Hz, 1H), 3.04 (s, 3H); Mass spectrum m/z: 553.40 (M+H).

Example 150:4-Chloro-N-[5-chloro-6-methyl-2-(2-methylsulfanyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution ofN-(2-bromo-5-chloro-6-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(255 mg, 0.5 mmol) in anhydrous THF (3 mL) was added 2Misopropylmagnesiumchloride in THF (600

L, 1.2 mmol) at −40° C. It was then warmed to 0° C. and stirred at thesame temperature for 1 h and thenN-Methoxy-N-methyl-2-methylsulfanyl-benzamide (422 mg, 1.00 mmol) wasadded in and the progress of the reaction was followed by LCMS. Thereaction mixture was warmed to room temperature and stirred overnight(18 h). It was then quenched with saturated aqueous NH₄Cl (2 mL), andextracted with EtOAc. The combined extracts were dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography (ISCO) to provide4-chloro-N-[5-chloro-6-methyl-2-(2-methylsulfanyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.Mass spectrum m/z: 601.4 (M+Na).

Example 151:4-Chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-6-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution of4-chloro-N-[5-chloro-6-methyl-2-(2-methylsulfanyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(100 mg, 0.17) in CH₂Cl₂ (5 mL) was added m-CPBA (125 g, 75% by wt, 0.54mmol) in one portion and the progress of the reaction was monitored byLCMS. After overnight stirring at room temperature, the reaction mixturewas quenched with pyridine (200

L) and reaction mixture was purified by reverse phase HPLC to provide4-chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-6-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.Mass spectrum m/z: 633.4 (M+Na).

Example 152:4-Chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-6-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture4-chloro-N-[5-chloro-2-(2-methanesulfonyl-benzoyl)-6-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(40 mg, 0.07 mmol) in 4M HCl in dioxane (2 mL), and water (1 mL) washeated at 100° C. for 4 h and then it was stirred at room temperatureovernight. The reaction mixture was concentrated to dryness underreduced pressure and it was treated with aqueous NaHCO₃ to adjust pH to5-6 and extracted with EtOAc. The combined extracts were dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by flash column chromatography on silica gel to provide thedesired product. ¹H NMR (400 MHz, CDCl₃) δ 10.93 (s, 1H), 8.21 (s, 1H),8.15 (s, 1H), 7.98-7.96 (m, 2H), 7.70-7.62 (m, 3H), 7.33-7.31 (m, 1H);Mass spectrum m/z: 567.4.0 (M+H).

Example 153:4-Chloro-N-[5-chloro-2-(2-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

4-Chloro-N-[5-chloro-2-(2-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidewas prepared according to procedure described in example 29 from2,N-dimethoxy-N-methyl-benzamide. Mass spectrum m/z: 571.0 (M+Na).

Example 154:4-Chloro-N-[5-chloro-2-(5-fluoro-2-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

4-Chloro-N-[5-chloro-2-(5-fluoro-2-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidewas prepared according to procedure described in example 29. Massspectrum m/z: 589.3 (M+Na).

Example 155:4-Chloro-N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

4-Chloro-N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidewas prepared according to procedure described in example 29. Massspectrum m/z: 589.0 (M+H).

Example 156:4-Chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

4-Chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.was prepared according to procedure described in example 29. Massspectrum m/z: 585.0 (M+H).

Example 157:4-Chloro-N-[5-chloro-2-(2-methoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to the procedure described inExample 149. ¹H NMR (400 MHz, CDCl₃) δ 10.81 (s, 1H), 8.24 (d, J=2.0 Hz,1H), 8.15-8.14 (m, 2H), 7.95 (dd, J=8.4, 2.0 Hz, 1H), 7.60 (d, J=8.4 Hz,1H), 7.51-7.47 (m, 1H), 7.32-7.30 (m, 1H), 7.05-7.01 (m, 1H), 6.90 (d,J=8.4 Hz, 1H), 3.52 (s, 3H); Mass spectrum m/z: 505.2 (M+H).

Example 158:4-Chloro-N-[5-chloro-2-(5-fluoro-2-methoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to the procedure described inExample 149. ¹H NMR (400 MHz, CDCl₃) δ 10.76 (s, 1H), 8.24 (d, J=2.0 Hz,1H), 8.15-8.14 (m, 2H), 7.96 (dd, J=8.0, 2.0 Hz, 1H), 7.62 (d, J=8.4 Hz,1H), 7.25-7.16 (m, 1H), 7.05-7.03 (m, 1H), 6.87-6.84 (m, 1H), 3.51 (s,3H); Mass spectrum m/z: 505.2 (M+H).

Example 159:4-Chloro-N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to the procedure described inExample 149. ¹H NMR (400 MHz, CDCl₃) δ 11.10 (s, 1H), 8.23 (d, J=2.4 Hz,1H), 8.18 (d, J=2.0 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 8.00 (dd, J=8.4,2.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.35-7.41 (m, 1H), 6.70-6.75 (m,2H), 3.68 (s, 3H); Mass spectrum m/z: 523.0 (M+H).

Example 160:4-Chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared according to the procedure described inExample 149. ¹H NMR (400 MHz, CDCl₃) δ 11.32 (s, 1H), 8.17-8.22 (m, 3H),8.13 (dd, J=8.0, 2.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.25-7.32 (m, 1H),6.84 (d, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 3.50 (s, 3H), 2.06 (s,3H); Mass spectrum m/z: 519.0 (M+H).

Example 161: 5-Chloro-2-iodo-3-nitro-pyridine

To a stirred mixture of 2-bromo-5-chloro-3-nitro-pyridine (2.5 g, 10.5mmol) in anhydrous DMF (20 mL) was added NaI (12.0 g, 80 mmol) was addedin one portion and the resulting mixture was heated at 95-100° C. for 2days. The reaction mixture was cooled to room tempearture and pouredinto water. It was then extracted with EtOAc and the combined extractswere washed with aqueous 10% Na₂S₂O₃. The combined extracts were dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residuewas purified by flash column chromatography on silica gel to provide5-Chloro-2-iodo-3-nitro-pyridine. Mass spectrum m/z: 285.2 (M+H).

Example 162:(5-Chloro-3-nitro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanol

To a stirred solution of 5-Chloro-2-iodo-3-nitro-pyridine (2.5 g, 8.77mmol) in anhydrous THF (20 mL) at −78° C. was added 2Mphenylmagnesiumchloride in THF (4.8 mL, 9.6 mmol) and stirred at thesame temperature for 30 minutes and then2,4-Dimethyl-pyridine-3-carbaldehyde (1.82 g, 13.15 mmol) was added inone portion and the progress of the reaction was followed by LCMS. Thereaction mixture was warmed to room temperature and stirred overnight(18 h). It was then quenched with saturated aqueous NH₄Cl (10 mL), andextracted with EtOAc. The combined extracts were washed with aqueousNaHCO₃, brine, and then dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by flash columnchromatography to(5-Chloro-3-nitro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanol.Mass spectrum m/z: 294.4 (M+H).

Example 163:(5-Chloro-3-nitro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone

A mixture of(5-chloro-3-nitro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanol(1.46 g) and Dess-Martin periodinane (2.52 g, 5.91 mmol) in CH₂Cl₂ (15mL) at room temperature was stirred for 5 h. A mixture of 10% aqueousNa₂S₂O₃ (10 mL) and saturated aqueous NaHCO₃ (10 mL) was then added andthe biphasic mixture vigorously stirred for 30 min. The phases were thenseparated and the aqueous portion extracted with CH₂Cl₂. The combinedorganic extracts were washed with saturated aqueous NaHCO₃, then brine,dried (Na₂SO₄) and filtered. The filtrate was concentrated under reducedpressure and the residue purified by flash column chromatography oversilica gel to provide(5-chloro-3-nitro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone.Mass spectrum m/z: 292.3 (M+Na).

Example 1648:(3-Amino-5-chloro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone

To a mixture of iron powder (220 mg, 4.0 mmol) in 4 ml of acetic acid at80° C. was slowly added a solution of(3-Nitro-5-chloro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone(260 mg, 0.89 mmol) in 2 ml of acetic acid. After the completion ofaddition the mixture was stirred at 80° C. for half an hour and thencooled. The mixture was diluted with ethyl acetate, filtered throughcelite and the filtrate was concentrated. The residue was purified byflash column (50% ethyl acetate in hexane) to afford 140 mg of titlecompound as off-white solid. MS: (M+H)/z=262.0.

Example 165:3,4-Dichloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-benzenesulfonamide

To a solution of(3-Amino-5-chloro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanone(43 mg, 0.16 mmol) and 10 mg of dimethylaminopyridine in 1.0 ml ofpyridine was added 3,4-dichlorobenzenesulfonylchloride (70 mg, 0.28mmol). The mixture was stirred at 80° C. for 3 hours, cooled to roomtemperature and concentrated. The residue was directly purified by flashcolumn (50% ethyl acetate in hexane) or preparative HPLC (20-80%acetonitrile in water) to afford 18 mg of title compound as an off-whitesolid. MS: (M+H)/z=470.4.

Example 166: 5-methyl-3-nitro-pyridin-2-ylamine

Sulfuric acid (97%, 100 mL) was placed in a −10° C. bath and when theinternal temperature reached to 5° C., 2-amino-picoline (25 g, 231.2mmol) was added in small portions with stirring (in 1 h). The suspensionwas stirred at ambient temperature to dissolve rest of the solid. Theresulting solution was heated to 55° C. and 70% conc. HNO₃ (15.6 mL) wasadded dropwise while maintaining the internal temperature between 55-60°C. The mixture was stirred further 30 min after the addition, pouredinto crushed ice (800 g), stirred to get solution and treated with 40%aqueous NaOH solution at 0° C. to reach pH 9 and extracted with CHCl₃(3×250 mL). Combined organic layers were washed with brine (2×200 mL),dried (anhydrous Na₂SO₄) and concentrated under reduced pressure toafford 5-methyl-3-nitro-pyridin-2-ylamine (9.49 g) as yellow solid in27% yield. ESMS m/z (relative intensity): 154 (M+H)⁺ (100).

Example 167: 2-Bromo-5-methyl-3-nitro-pyridine

To concentrated HBr (48%, 28.6 mL) was added5-methyl-3-nitro-pyridin-2-ylamine (5 g, 32.6 mmol) in portions at 0° C.temperature with stirring. The mixture was stirred until the internaltemperature reached to −10° C., then bromine was added drop wise. Asolution of NaNO₂ (7.6 g, 110.84 mmol) in water (11 mL) was added slowlyto maintain the reaction mixture temperature below 0° C. The darkmixture (gas evolution was observed) was stirred for 1 h at 0° C. thenwas carefully treated (slow addition) with a solution of NaOH (12 g, 300mmol) in water (17 mL) while maintaining the internal temperature below20° C. The mixture was stirred for an additional 1 h, then was filtered,dried under vacuum for 6 h and purified by recrystallization using 95%EtOH to get pure 2-bromo-5-methyl-3-nitro-pyridine (1.96 g) as yellowsolid in 28% first crop yield. ESMS m/z (relative intensity): 217 (M+H)⁺(100).

Example 168: 2-Bromo-5-methyl-pyridin-3-ylamine

To Fe power (2.18 g, 39.0 mmol), AcOH (10 mL) was added drop wise andheated to 80° C. To it, a solution of 2-bromo-5-methyl-3-nitro-pyridine(1.96 g, 9.07 mmol) in AcOH (10 mL) was added slowly. After 30 min,reaction mixture was allowed to cool to room temperature and dilutedwith EtOAc (25 mL), filtered through a pad of celite. The filter cakewas washed with EtOAc (25 mL) and filterate was concentrated. Theresidual liquid was slowly treated with saturated aqueous NaHCO₃solution (70 mL), followed by small portions of solid NaHCO₃ toneutralize the AcOH, extracted with EtOAc (2×50 mL) and the extractswere dried (anhydrous Na₂SO₄) and concentrated under reduced pressure toget 2-bromo-5-methyl-pyridin-3-ylamine (1.45 g) as a brown solid in86.3% yield. ESMS m/z (relative intensity): 187 (M+H) (100).

Example 169:N-(2-Bromo-5-methyl-pyridin-3-yl)-4-chloro-3-trifluoromethylBenzenesulfonamide

A solution of 2-bromo-5-methyl-pyridin-3-ylamine (1 g, 5.38 mmol) and4-chloro-3-trifluoromethylbenzenesulfonylchloride (1.8 g, 6.46 mmol) inpyridine (5 mL) was stirred at 60° C. for 12 h. The mixture wasconcentrated under reduced pressure and to it, was added 1:1 EtOAc-10%aqueous HCl (50 mL). Aqueous layer was separated and extracted withEtOAc (2×50 mL). Combined EtOAc layers were washed with 10% aqueous HCl(50 mL), dried (anhydrous Na₂SO₄), concentrated and column purified(SiO₂, 50% EtOAc-hexanes) to obtainN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide(1.42 g) in 84% yield as a half white solid. ESMS m/z (relativeintensity): 429 (M+H)⁺ (100).

Example 170: N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N methoxymethyl-3-trifluoromethyl-benzenesulfonamide

A mixture ofN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide(1.4 g, 3.27 mmol), chloromethyl methyl ether (0.4 mL, 5.23 mmol) andK₂CO₃ (1.35 g, 9.81 mmol) in THF (20 mL) was stirred at room temperaturefor 3 h. The mixture was filtered and the filtrate was concentrated andpurified by flash chromatography (SiO₂, 20% EtOAc-hexanes) to affordN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(1.3 g) as a white solid in 84% yield. ESMS m/z (relative intensity):473 (M+H)⁺ (100).

Example 171:4-Chloro-N-{2-[(2,4-dimethyl-pyridin-3-yl)-hydroxy-methyl]-5-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(500 mg, 1.06 mmol) in THF (3 mL) under nitrogen atmosphere at −30° C.was added drop wise isopropylmagnesium chloride (2M solution in THF,1.27 mL, 2.54 mmol). The mixture was then stirred for 30 min at 0° C.followed by the addition of a solution of2,4-dimethyl-pyridine-3-carbaldehyde (271 mg, 2.01 mmol) at −30° C. Themixture was stirred at room temperature for 3 hours, quenched withsaturated aqueous NH₄Cl solution (5 mL) and extracted with EtOAc (2×25mL). Combined organic layers were washed with saturated aqueous NH₄Clsolution (25 mL), brine (25 mL), dried (anhydrous Na₂SO₄) andconcentrated under reduced pressure. Obtained residue was columnpurified (SiO₂, 50% EtOAc-hexanes) to obtain4-chloro-N-{2-[(2,4-dimethyl-pyridin-3-yl)-hydroxy-methyl]-5-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (288 mg) as yellow foam in 51% yield. ESMS m/z (relativeintensity): 530 (M+H)⁺ (100).

Example 172:4-Chloro-N-[2-(2,4-dimethyl-pyridine-3-carbonyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution of4-chloro-N-{2-[(2,4-dimethyl-pyridin-3-yl)-hydroxy-methyl]-5-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (280 mg, 0.53 mmol) in CH₂Cl₂ (5 mL) was added Dess-Martinperiodinane (403 mg, 0.95 mmol) and stirred for 3 h at room temperature.10% Na₂S₂O₃ (5 mL) and saturated aqueous NaHCO₃ solution (5 mL) wasadded and stirred for 30 min. Aqueous layer was separated and extractedwith EtOAc (2×25 mL). Combined organic layers were washed with saturatedaqueous NaHCO₃ solution (20 mL), brine (20 mL), dried (anhydrousNa₂SO₄), concentrated to obtain4-chloro-N-[2-(2,4-dimethyl-pyridine-3-carbonyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(277 mg) as thick yellow syrup in quantitative crude yield which wasused for further transformation without purification. ESMS m/z (relativeintensity): 528 (M+H)⁺ (100).

Example 173:4-Chloro-N-[2-(2,4-dimethyl-pyridine-3-carbonyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[2-(2,4-dimethyl-pyridine-3-carbonyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(260 mg, 0.49 mmol) in 4M HCl in dioxane (5 mL) and water (1 mL) wasrefluxed for 3 h. Reaction mixture was cooled to room temperature,evaporated to dryness and treated with saturated aqueous NaHCO₃ solutiontill pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried(anhydrous Na₂SO₄) and concentrated. The obtained residue was purifiedby flash chromatography (SiO₂, 70% EtOAc-hexanes) to afford4-chloro-N-[2-(2,4-dimethyl-pyridine-3-carbonyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(78 mg) as an off white solid (after lyophilization) in 33% yield. ESMSm/z (relative intensity): 484 (M+H)⁺ (100).

Example 174:4-Chloro-N-{2-[(2-chlorophenyl)-hydroxy-methyl]-5-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesufonamide

To a solution ofN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(500 mg, 1.06 mmol) in THF (3 mL) under nitrogen atmosphere at −30° C.was added drop wise isopropylmagnesium chloride (2M solution in THF,1.27 mL, 2.54 mmol). The mixture was then stirred for 30 min at 0° C.followed by the addition of a solution of 2-chlorobenzaldehyde (271 μL,2.01 mmol) at −30° C. The mixture was stirred at room temperature for 3hours, quenched with saturated aqueous NH₄Cl solution (5 mL) andextracted with EtOAc (2×25 mL). Combined organic layers were washed withsaturated aqueous NH₄Cl solution (25 mL), brine (25 mL), dried(anhydrous Na₂SO₄) and concentrated under reduced pressure. Obtainedresidue was column purified (SiO₂, 50% EtOAc-hexanes) to obtain4-chloro-N-{2-[(2-chlorophenyl)-hydroxy-methyl]-5-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(274 mg) as yellow foam in 48% yield. ESMS m/z (relative intensity): 535(M+H)⁺ (100).

Example 175:4-Chloro-N-[2-(2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution of4-chloro-N-{2-[(2-chlorophenyl)-hydroxy-methyl]-5-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (260 mg, 0.49 mmol) in CH₂Cl₂ (5 mL) was added Dess-Martinperiodinane (373 mg, 0.88 mmol) and stirred for 3 h at room temperature.10% Na₂S₂O₃ (5 mL) and saturated aqueous NaHCO₃ solution (5 mL) wasadded and stirred for 30 min. Aqueous layer was separated and extractedwith EtOAc (2×25 mL). Combined organic layers were washed with saturatedaqueous NaHCO₃ solution (20 mL), brine (20 mL), dried (anhydrousNa₂SO₄), concentrated to obtain4-chloro-N-[2-(2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(260 mg) as thick yellow syrup in quantitative crude yield which wasused for further transformation without purification. ESMS m/z (relativeintensity): 501 (M-MeOH) (100).

Example 176:4-Chloro-N-[2-(2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethylBenzenesulfonamide

A mixture of4-chloro-N-[2-(2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(260 mg, 0.49 mmol) in 4M HCl in dioxane (5 mL) and water (1 mL) wasrefluxed for 3 h. Reaction mixture was cooled to room temperature,evaporated to dryness and treated with saturated aqueous NaHCO₃ solutiontill pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried(anhydrous Na₂SO₄) and concentrated. The obtained residue was purifiedby flash chromatography (SiO₂, 70% EtOAc-hexanes) to afford4-chloro-N-[2-(2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(106 mg) as a white solid (after lyophilization) in 45% yield. ESMS m/z(relative intensity): 489 (M+H)⁺ (100).

Example 177:2-{5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-benzoicAcid

To a solution ofN-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(250 mg, 0.50 mmol) in 4.0 ml of THF under nitrogen atmosphere at 0° C.was added drop-wise 0.6 ml (1.2 mmol) of isopropylmagnesium chloride.The mixture was then stirred for 20 min at 0° C. followed by addition ofa solution of phthalic anhydride (148 mg, 1.0 mmol) in 1 ml of DCM. Themixture was stirred at room temperature overnight, quenched withsaturated ammonium chloride and extracted with ethyl acetate. Afterconcentration the residue was purified by flash chromatograph (70% ethylacetate in hexane) to afford 80 mg of title compound as an off whitesolid. MS: (M+H)/z=564.0, (M−32)/z=532.0.

Example 178:2-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-benzoicAcid

A mixture of2-{5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-benzoicacid (150 mg, 0.27 mmol) in 3 ml of 4M HCl in dioxane and 1 mL of waterwas refluxed for 2 hours. After cooling to room temperature the mixturewas concentrated and then diluted with water. Sodium bicarbonate wasadded until pH was 6. The mixture was extracted with ethyl acetate,dried and concentrated. The residue was further purified via flashcolumn (70% ethyl acetate in hexane) to afford 60 mg of title compoundas an off white solid. MS: (M+H)/z=519.4.

Example 179:4-Chloro-N-[5-chloro-2-(4-oxo-3,4-dihydro-phthalazin-1-yl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of2-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-benzoicacid (18 mg, 0.0347 mmol) and 2.3 mg of hydrazine hydrate in 1.0 ml ofethanol was refluxed for 4 hours. After cooled to room temperature themixture was concentrated and the residue was purified via preparativeTLC to afford 12 mg of title compound as a white powder. MS:(M+H)/z=515.2.

Example 180: 2-Oxazol-2-yl-benzoic Acid Methyl Ester

Step 1

To a solution of phthalic acid monomethyl ester (1.8 g, 10 mmol) and0.020 ml of DMF in 10 ml of DCM was added oxalyl chloride (1.52 g, 12mmol). The mixture was stirred at room temperature for 2 hours and thenconcentrated. The residue was used directly for the step 2.

Step 2

A mixture of 2-Chlorocarbonyl-benzoic acid methyl ester (1.3 gram, 6.56mmol), 1H-triazole (0.42 ml, 7.22 mmol) and potassium carbonate (2.78 g,20 mmol) in 12 ml of tetramethylene sulfone was heated at 140° C. forhalf an hour. The mixture was cooled, diluted with ethyl acetate, washedwith water 5 times, and dried. After concentration the crude waspurified by flash column (50% ethyl acetate in hexane) to afford 250 mgof 2-Oxazol-2-yl-benzoic acid methyl ester as a light yellow liquid. MS:(M+H)/z=204.1.

Example 181: N-Methoxy-N-methyl-2-oxazol-2-yl-benzamide

Step 1

A mixture of 2-Oxazol-2-yl-benzoic acid methyl ester (200 mg) in amixture of 5 mL of methanol and 10 ml of 1M NaOH was stirred for 3 hoursat room temperature. The mixture was neutralized with 2N HCl until pHwas 4. The mixture was concentrated and 30 ml of ethyl acetate was addedand the resulting mixture was filtrated, the filtrate was concentratedand the residue was used directly at step 2.

Step 2

2-Oxazol-2-yl-benzoyl chloride was made by according to the previouslydescribed procedure.

Step 3

To a mixture of 2-Oxazol-2-yl-benzoyl chloride (104 mg, 0.5 mmol), DIEA(0.26 mL, 1.5 mmol) in 2 ml of DCM was added N,O-dimethylhydroxylaminehydrochloride (59 mg, 0.6 mmol). The mixture was stirred at roomtemperature for 2 hours, washed with dilute HCl solution followed bybrine. Concentration of the organic layer afforded 100 mg ofN-Methoxy-N-methyl-2-oxazol-2-yl-benzamide as a sticky light yellowliquid. MS: (M+H)/z=233.1.

Example 182:4-Chloro-N-[5-chloro-2-(2-oxazol-2-yl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(125 mg, 0.25 mmol) in 2.0 mL of THF under nitrogen atmosphere at 0° C.was added drop-wise 0.3 ml (0.6 mmol) of isopropylmagnesium chloride.The mixture was then stirred for 20 min at 0° C. followed by addition ofN-Methoxy-N-methyl-2-oxazol-2-yl-benzamide (100 mg, 0.43 mmol). Themixture was stirred at room temperature overnight, quenched withsaturated ammonium chloride and extracted with ethyl acetate. Afterconcentration the residue was purified by flash chromatograph (30% ethylacetate in hexane) to afford 30 mg of title compound as an off whitesolid. MS: (M+H)/z=586.1.

Example 183:4-Chloro-N-[5-chloro-2-(2-oxazol-2-yl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-Chloro-N-[5-chloro-2-(2-oxazol-2-yl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(15 mg) in 2 mL of 4M HCl in dioxane and 1 mL of water was refluxed for2 hours. After cooling to rt the mixture was concentrated, diluted withwater and then sodium bicarbonate was added until pH was 6. The mixturewas extracted with ethyl acetate, dried and concentrated. The residuewas purified via flash column (35% ethyl acetate in hexane) to afford8.0 mg of title compound as an off white solid. MS: (M+H)/z=542.3.

Example 184:N-[2-(2-Bromo-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(250 mg, 0.50 mmol) in 4.0 ml of THF under nitrogen atmosphere at 0° C.was added drop-wise 0.6 mLl (1.2 mmol) of isopropylmagnesium chloride.The mixture was then stirred for 20 min at 0° C. followed by addition ofa solution of 2-Bromo-N-methoxy-N-methyl-benzamide (244 mg, 1.0 mmol) in1 mL of THF. The mixture was stirred at room temperature overnight,quenched with saturated ammonium chloride and extracted with ethylacetate. After concentration of the solvent the residue was purified byflash chromatograph (20% ethyl acetate in hexane) to afford 180 mg oftitle compound as an off white solid. MS: (M+Na)/z=621.2,(M−32)/z=567.0.

Example 185:N-[2-(2-Bromo-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide

A mixture ofN-[2-(2-Bromo-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(100 mg, 0.167 mmol) in 3 ml of 4M HCl in dioxane and 1 mL of water wasrefluxed for 3 hours. After cooling to rt the mixture was concentrated,diluted with water and then sodium bicarbonate was added until pH was 6.The mixture was extracted with ethyl acetate, dried and concentrated.The residue was further purified via flash column (30% ethyl acetate inhexane) to afford 50 mg of title compound as an off white solid. MS:(M+H)/z=555.3, (M+Na)/z=575.3.

Example 186:4-Chloro-N-[5-chloro-2-(1-hydroxy-2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution of4-Chloro-N-[5-chloro-2-(2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(100 mg, 0.182 mmol) in 3.5 mL of DCM was added meta-chloroperoxybenzoicacid (77%, 95 mg, 0.424 mmol). After thirty hours the crude mixture wasadded 1.0 ml of pyridine and the mixture was concentrated. The mixturewas diluted with ethyl acetate, washed with water, dried over sodiumsulfate and concentrated. The crude was used at next step without anyfurther purification. MS: (M+H)/z=564.0.

Example 187:4-Chloro-N-[5-chloro-2-(1-hydroxy-2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A solution of4-Chloro-N-[5-chloro-2-(1-hydroxy-2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(21 mg) in 6 ml of HCl (4M in dioxane) and 2 mL of water was refluxedfor 2 hours. After cooling to rt the mixture was concentrated and wasadded 3 mL of water. Sodium bicarbonate was added until the final pH was6. The mixture was extracted with ethyl acetate, dried and concentrated.The residue was further purified via short flash column (8% methanol inDCM) to afford 7.9 mg of title compound as an off white solid. MS:(M+H)/z=520.0.

Example 188:4-Chloro-N-[5-chloro-2-(2-chloro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

To a magnetically stirred solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-(trifluoromethyl)-benzenesulfonamide(1.5 g, 3.03 mmol) in anhydrous THF (15 mL) was added 2Misopropylmagnesium chloride in THF (3.3 mL, 6.6 mmol) at −20° C. Thetemperature was allowed to slowly rise to 10° and then2-chloro-N-methoxy-N-methylbenzamide (1.2 g, 6.0 mmol) was added and theprogress of the reaction was followed by LCMS. The reaction mixture waswarmed to room temperature and stirred for 16 h. It was then quenchedwith saturated aqueous NH₄Cl (50 mL), and extracted with ethyl acetate(3×100 mL). The combined extracts were dried (MgSO₄), filtered andconcentrated. The residue was purified by chromatography on silica gelusing ethyl acetate-hexane mixtures (2:98, 5:95) to provide4-chloro-N-[5-chloro-2-(2-chloro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidemass spectrum m/z 574.8 (M+Na); 521.0 (M−31).

The intermediate MOM derivative (1.1 g, 1.99 mmol) was stirred in water(2.5 mL) and 4N HCl in dioxane (12 mL) and heated at 100° C. (oil bath)for 2.5 h. LCMS indicated complete reaction; the reaction wasconcentrated and the residue was neutralized with saturated aqueoussodium bicarbonate and extracted with ethyl acetate (3×80 mL). Theextracts were dried (MgSO₄), filtered, and chromatographed on silica gelusing EtOAc-hexane mixtures (2:98, 5:95) to provide pure product. massspectrum m/z 510.9 (M+H); 532.9 (M+Na).

Example 189: 5-Chloro-2-(2,6-dimethyl-phenoxy)-pyridin-3-ylamine

2-Bromo-3-nitro-5-chloropyridine (4.8 g, 20 mmol) and 2,6-dimethylphenol(5.0 g, 41 mmol) were magnetically stirred in dry DMF (65 mL) andpotassium carbonate (11.0 g, 80 mmol) was added. The mixture was heatedat 50° C. for 4 days, allowed to cool to room temperature and added toice; the product was extracted with ethyl acetate (3×100 mL). Theextracts were washed with saturated aqueous NaHCO₃ and dried (MgSO₄),filtered and concentrated to provide the desired product.

The nitro compound (4.5 g, 16 mmol) was dissolved in glacial acetic acid(80 mL) and this solution was added dropwise to a well-stirredsuspension of iron powder (4.5 g, 80 mmol) in glacial acetic acid (40mL) heated in an oil bath at 80° C. under nitrogen. The progress of thereaction was checked by LCMS. After 20 min, the reaction was allowed tocool and was diluted with ethyl acetate (120 mL). The resulting mixturewas vacuum filtered through a pad of Celite, the filter cake was washedwith ethyl acetate (100 mL) and the filtrate was concentrated. Theresidue was slowly treated with saturated aqueous sodium bicarbonate,followed by the addition of small portions of solid sodium bicarbonateto neutralize the acetic acid. The mixture was extracted using ethylacetate (3×150 mL) and the extracts were dried (MgSO₄), filtered andconcentrated (rotovap). The product was isolated as a crystalline solidafter drying (vacuum). mass spectrum m/z 251.3 (M+H).

Example 190:4-Chloro-N-[5-chloro-2-(2,6-dimethyl-phenoxy)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The starting aniline was magnetically stirred in pyridine and reactedwith 4-chloro-3-(trifluoromethyl)benzenesulfonyl chloride according tothe procedure described in Example 94 to provide the desired product.mass spectrum m/z 491.4 (M+1).

Example 191:2-Chloro-N-[5-chloro-2-(2,6-dimethyl-phenoxy)-pyridin-3-yl]-5-trifluoromethyl-benzenesulfonamide

The starting aniline was magnetically stirred in pyridine and reactedwith 2-chloro-5-(trifluoromethyl)benzenesulfonyl chloride according tothe procedure described in Example 94 to provide the desired product.mass spectrum m/z 491.4 (M+H).

Example 192:4-Chloro-N-[5-chloro-2-(2-hydroxymethyl-4-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamideand4-Chloro-N-[5-chloro-2-(4-hydroxymethyl-2-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The starting N-oxide (1.0 g, 1.92 mmol) was dissolved in methylenechloride (35 mL) and cooled in an ice bath. Trifluoroacetic anhydride(0.7 mL, 1.05 g) was added dropwise to the magnetically stirredsolution, and more (0.7 mL) was added after 5 min. The deep red reactionmixture was stirred 16 h at room temperature; no starting material wasdetected by LCMS. The reaction was cooled to 0° C. and water (20 mL) wasadded dropwise, then the mixture was allowed to come to roomtemperature. The layers were separated and the water layer was extractedwith methylene chloride (2×25 mL). The combined organic layer was dried(MgSO₄), filtered and concentrated to give a red oil. Chromatography onsilica gel (ethyl acetate-hexane) using a 5:95 to 95:5 gradient gaveseveral mixed fractions and a few fractions each of the two products.Major Isomer:4-chloro-N-[5-chloro-2-(2-hydroxymethyl-4-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamidemass spectrum m/z 520.4 (M+1). Minor Isomer:4-chloro-N-[5-chloro-2-(4-hydroxymethyl-2-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide.mass spectrum m/z 520.4 (M+1).

Example 193:5-Chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid

A 100 mL round-bottom flask was charged with the above3-amino-2-cyano-5-chloropyridine (8.95 g, 61.54 mmol),4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (19.6 g, 80 mmol),and pyridine (50 mL). The resultant solution was heated to 60° C. andstirred for overnight. The pyridine was removed in vacuo and dioxane(200 mL) was added, followed by NaOH (28 g, 0.70 mol). The mixture wasstirred under reflux for two days. The solvent was subsequently removedin vacuo and ice (100 g) was added and the pH adjusted to 2-3 with concHCl. The resultant solid was filtered and washed with water twice andwas dried in vacuo to afford the light yellow solid. This solid wasdissolved in EtOAc and any insoluble solid was filtered off. Thefiltrate was washed with brine, dried (Na₂SO₄), filtered and thefiltrate was concentrated under reduced pressure to afford5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (16.5 g): (M+H)⁺ expect 395.0, found 395.0.

Example 194:5-Chloro-3-(4-chloro-3-methyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid

5-Chloro-3-(4-chloro-3-methyl-benzenesulfonylamino)-pyridine-2-carboxylicacid was prepared from 3-amino-2-cyano-5-chloropyridine and4-chloro-3-methyl-benzenesulfonyl chloride following a procedure asdescribed in example 116, step 3. MS m/z: 361.0 (M+H)⁺.

Example 195:3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylicAcid

A 25 mL round-bottom flask was charged with the above3-amino-2-cyano-5-chloropyridine (1.04 g, 6.8 mmol),4-tert-butyl-benzenesulfonyl chloride (2.09 g, 8.8 mmol), and pyridine(6 mL). The resultant solution was heated to 70° C. and stirred for 5 h.The pyridine was removed in vacuo and EtOH (70%, 20 mL) was added,followed by NaOH (3.20 g, 0.8 mol). The mixture was stirred underrefluxed for 12 h. The solvent was subsequently removed in vacuo and ice(10 g) was added and the pH adjusted to 2-3 with conc HCl. The resultantaqueous solution was extracted with EtOAc, washed with brine, dried overMgSO₄, and concentrated under reduced pressure. The light yellow solidwas further crystallized from EtOAc/hexane (1:1) to afford the desiredacid as white needles (734.8 mg): MS (ES) (M+H)⁺ expected 369.1, found369.0.

Example 196:4-Chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(10.6 mg, 21.4 mmol) in THF (80 mL) under nitrogen atmosphere at −40° C.was added isopropylmagnesium chloride (25 mL, 50 mmol, 2M in THF). Themixture was then warmed to 0° C. over 30 min and DMF (4 mL, 51 mmol) wasadded. The reaction mixture was stirred at room temperature overnight,quenched with saturated aqueous ammonium chloride, and followed by HCl(1M) to pH ˜3. The mixture was extracted with ethyl acetate, dried, andconcentrated to provide4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.MS: (M+H)/z=442.9.

The unpurified aldehyde from the previous reaction was magneticallystirred in dioxane (20 mL), water (20 mL), and 4N HCl in dioxane (40mL); and heated at 80° C. (oil bath) overnight. LCMS indicated completereaction; the reaction was concentrated and the residue was neutralized(pH 6) with aqueous sodium bicarbonate and extracted with ethyl acetate(3×80 mL). The extracts were dried (Na₂SO₄), filtered, and purified byflash column chromatography on silica gel using ethyl acetate-hexane toprovide4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide.MS: (M+H)/z=398.9.

Example 197:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid methoxy-methyl-amide

5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (15.8, 38 mmol), N,O-dimethyl hydroxylamine hydrochloride (11.1 mg,114 mmol), DIEA (41 mL, 228 mmol) methyl-m-tolyl-amine (44 mg, 0.36mmol), and BOP (69 mg, 49 mmol), were reacted according to the procedureD for the synthesis of5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-picolinicamides at 50° C. The reaction mixture was quenched with 1 (M) HCl,extracted with EtOAc, and the organic portions were washed with 1 (M)aqueous HCl, NaHCO₃ and brine. The combined organic extracts were dried(Na₂SO₄), filtered and concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography to afford5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methoxy-methyl-amide: MS m/z: (M+H) 458.0.

Example 198:5-Chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid methoxy-methyl-amide

5-Chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methoxy-methyl-amide was prepared from5-Chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid as described in example 144.

Example 199:5-Chloro-3-[methoxymethyl-(4-methyl-3-trifluoromethyl-benzenesulfonyl)-amino]-pyridine-2-carboxylicAcid methoxy-methyl-amide

To a mixture of sodium hydride (164 mg, 4.10 mmol) in 5 mL of THF wasadded a mixture of5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methoxy-methyl-amide (1.50 g, 3.42 mmol) and chloromethyl methylether (0.388 mL, 5.13 mmol) in 5 mL of THF. The mixture was stirred atroom temperature overnight. After the removal of the solvents theresidue was purified by flash column (20% ethyl acetate in hexane) toafford 1.50 grams of the title compound as a white solid: (M⁺+H) expect482.0, found 482.0.

Example 200:5-Chloro-3-[methoxymethyl-(4-chloro-3-trifluoromethyl-benzenesulfonyl)-amino]-pyridine-2-carboxylicAcid methoxy-methyl-amide

To a suspension of sodium hydride (314 mg, 7.86 mmol) in 8 mL of THF wasadded a mixture of5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methoxy-methyl-amide (3.0 g, 6.55 mmol) and chloromethyl methylether (0.741 mL, 9.825 mmol) in 8 mL of THF. The mixture was stirred atroom temperature overnight. After the removal of the solvents theresidue was purified by flash column (20% ethyl acetate in hexane) toafford 2.70 grams of the title compound as a white solid. (M+H)⁺ expect502.0, found 502.0.

Example 201:4-Chloro-N-[5-chloro-2-(2-chloro-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Following the procedure for example 116, step 2;5-chloro-2-iodo-3-nitro-pyridine was converted to5-chloro-2-iodo-pyridin-3-ylamine.

Following the procedure for example 24,4-chloro-N-(5-chloro-2-iodo-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamidewas synthesized from 5-chloro-2-iodo-pyridin-3-ylamine and4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.

Example 202: N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

A mixture ofN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide(1.4 g, 3.27 mmol), chloromethyl methyl ether (0.4 mL, 5.23 mmol) andK₂CO₃ (1.35 g, 9.81 mmol) in THF (20 mL) was stirred at room temperaturefor 3 h. The mixture was filtered and the filtrate was concentrated andpurified by flash chromatography (SiO₂, 20% EtOAc-hexanes) to affordN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(1.3 g) as a white solid in 84% yield. ESMS m/z (relative intensity):473 (M+H)⁺ (100).

Example 203:N-(2-Bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide

N-(2-Bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamidewas prepared fromN-(2-bromo-5-chloro-pyridin-3-yl)-4-methyl-3-trifluoromethyl-benzenesulfonamideaccording to the procedure described in example 149.

Example 204: 3-Methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carboxylicAcid methoxy-methyl-amide

To a stirred solution of 2-amino-3-nitro-benzoic acid methyl ester (2.0g, 10.2 mmol) in THF (10 mL) at 0° C. was added Et₃N (4.76 mL, 33 mmol)was added followed by a solution of trifluoroacetic anhydride (3.3 g,1.6 mmol) in THF (5 mL) dropwise. The resulting mixture was warmed toroom temperature and stirred at room temperature overnight. It wasquenched with water (2 mL) and resulting mixture was concentrated underreduced pressure. Cold water was added to the residue to cause whitewhich filtered and washed water to provide3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester as awhite solid. MS m/z: 260.9 (M+H).

To a stirred suspension of NaH (112 mg, 2.80 mmol, 60% dispersion inmineral oil) in DMF (5 mL) at 0° C. was added3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester (750mg, 2.55 mmol) portion wise. The resulting mixture was stirred for 1 h,then MeI (175 mL, 2.80 mmol) was added and the progress of the reactionwas followed by LCMS. Upon consumption of3-nitro-2-(2,2,2-trifluoro-acetylamino)-benzoic acid methyl ester, thereaction mixture was quenched with aqueous NH₄Cl, and extracted withEtOAc. The combined extracts were washed with brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by chromatography on silica gel using ethyl acetate-hexane toprovide 2-[methyl-(2,2,2-trifluoro-acetyl)-amino]-3-nitro-benzoic acidmethyl ester. MS m/z: 275.0 (M+H)⁺.

A mixture of 2-[methyl-(2,2,2-trifluoro-acetyl)-amino]-3-nitro-benzoicacid methyl ester (1.7 g, 5.5 mmol) and 5M aqueous NaOH (5 mL) in THF(10 mL) was stirred at 50° C. for several hours. The mixture wasacidified with 4M HCl and extracted with EtOAc to provide2-methylamino-3-nitro-benzoic acid. MS m/z: 197.0 (M+H)⁺.

A mixture of 2-methylamino-3-nitro-benzoic acid and 10% Pd/C (300 mg) inEtOAc (5 mL) and EtOH (5 mL) was stirred in an atmosphere of hydrogenover night. The mixture was filtered though a pad of Celite and thefilter cake was washed with EtOAc. The filtrate was concentrated underreduced pressure to provide 3-amino-2-methylamino-benzoic acid.

To a mixture of 3-amino-2-methylamino-benzoic acid (50 mg, 0.30 mmol)and DIEA (138

L, 0.75 mmol) in THF was added triphosgene (106 mg, 0.41 mmol). Theresulting mixture was stirred at room temperature for 6 h, thenN,O-dimethyl hydroxylamine hydrochloride (88 mg, 0.9 mmol) and DIEA (276

L, 1.5 mmol) was added. The resulting mixture was stirred at roomtemperature overnight, then quenched with saturated aqueous NH₄Cl (10mL), and extracted with EtOAc (3×15 mL). The combined extracts werewashed with brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by chromatography on silicagel using MeOH/CH₂Cl₂ to provide2-amino-N-methoxy-N-methyl-3-(3-N,O-dimethyl-ureido)-benzamide. MS m/z:297.0 (M+H)⁺.

A mixture of 2-amino-N-methoxy-N-methyl-3-(3-N,O-dimethyl-ureido)-benzamide and K₂CO₃ was heated at reflux for 48 h.The resulting mixture was neutralized with saturated aqueous NH₄Cl (10mL), and extracted with EtOAc (3×15 mL). The combined extracts werewashed with brine, dried (Na₂SO₄), filtered, and concentrated underreduced pressure. The residue was purified by chromatography on silicagel using MeOH/CH₂Cl₂ to provide3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carboxylic acidmethoxy-methyl-amide. MS m/z: 237.0 (M+H)⁺.

Example 205:N-[5-Chloro-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide

N-[5-Chloro-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamidewas prepared from3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carboxylic acidmethoxy-methyl-amide andN-(2-bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamideaccording to previously described procedure in example 29, step 1. Theproduct was purified by flash column chromatography on silica gel usingethyl acetate-hexane. MS m/z: 569.0 (M+H)⁺.

Example 206:N-[5-Chloro-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide

A solution ofN-[5-Chloro-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamidein 4M HCl in dioxane (2 mL) and water (1 mL) was heated at 95° C. for 7h, then MeOH (1 mL) and water (2 mL) was added and heating was continuedovernight. The resulting mixture was purified by HPLC to provideN-[5-chloro-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide.¹H NMR (400 MHz, CDCl₃) δ 10.94 (s, 1H), 8.28 (d, J=2.0 Hz, 1H), 8.21(d, J=1.6 Hz, 1H), 8.08 (s, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.42 (d, J=8.0Hz, 1H), 7.19-7.17 (m, 1H), 7.01 (t, J=7.6 Hz, 1H), 6.82 (d, J=7.6 Hz,1H), 3.10 (s, 3H), 2.53 (s, 3H); MS m/z 524.9 (M+H)⁺.

Example 207:N-[5-Chloro-2-(2-methylamino-pyridine-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide

To a stirred solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-3,4-dimethyl-benzenesulfonamide(4.71 mg, 10 mmol) in anhydrous THF (40 mL) under nitrogen was added 2Misopropylmagnesium chloride in THF (11 mL, 22 mmol) at −20° C. It wasthen warmed to 0° C. over 45 minutes the exchange of bromo-functionalgroup with magnesium reagent was followed by LCMS. Weinreb amide (1.99g, 12 mmol) was added with a syringe in one portion and the reactionmixture was slowly warmed to room temperature over 5 h. The progress ofthe reaction was followed by LCMS. After 2 h stirring at roomtemperature, the resulting mixture was neutralized with saturatedaqueous NH₄Cl (10 mL), and extracted with EtOAc (3×15 mL). The combinedextracts were washed with aqueous NaHCO₃, brine, dried (Na₂SO₄),filtered, and concentrated under reduced pressure. The residue waspurified by chromatography on silica gel using MeOH/CH₂Cl₂ to provideN-[5-chloro-2-(pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide.Mass spectrum m/z: 500.0 (M+H)⁺.

To a stirred solution ofN-[5-chloro-2-(pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide(3.0 g, 6.0 mmol) in CH₂Cl₂ (20 mL) was added peracetic acid (2.1 mL,9.0 mmol) at room temperature. The reaction mixture was stirred at roomtemperature for 20 h. At this time, saturated aqueous NaHSO₃ (5 mL) andthe biphasic mixture was stirred for 5 minutes. The resulting mixturewas extracted with EtOAc and washed with aqueous NaHCO₃ and brine. Thecombined organic extract was dried, filtered and then concentrated underreduced pressure. The residue was purified by flash columnchromatography to provideN-[5-chloro-2-(1-oxy-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide.Mass spectrum m/z: 516.0 (M+H)⁺.

To a stirred solution of acetamide (412 mg, 5.64 mmol) and 2,6-lutidine(1.3 mL, 11.28 mmol) in CH₂Cl₂ at 0° C. was added oxalyl chloride (505

L, 5.64 mmol) drop-wise. After 15 minutes, stirring at the sametemperatureN-[5-chloro-2-(1-oxy-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide(971 mg, 1.88 mmol) was added stirred overnight at room temperature. Thereaction mixture was poured into an aqueous solution of NaHCO₃ andextracted with EtOAc (2×30 mL). The combined organic extract was dried,filtered and then concentrated under reduced pressure. The residue waspurified by flash column chromatography to provideN-(4-{5-chloro-3-[methoxymethyl-(4-methyl-3-trifluoromethyl-benzenesulfonyl)-amino]-pyridine-2-carbonyl}-pyridin-2-yl)-N-methyl-acetamide.Mass spectrum m/z: 571.0 (M+H)⁺.

A solution ofN-(4-{5-chloro-3-[methoxymethyl-(4-methyl-3-trifluoromethyl-benzenesulfonyl)-amino]-pyridine-2-carbonyl}-pyridin-2-yl)-N-methyl-acetamidein 4M HCl in dioxane (4 mL) and water (2 mL) was heated at 95° C. for 4h, then MeOH (2 mL) and 2M aqueous HCl (5 mL) was added and heating wascontinued overnight. Upon cooling of the reaction mixtureN-[5-chloro-2-(2-methylamino-pyridine-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamidewas obtained was obtained as pale yellow solid. Mass spectrum m/z: 485.0(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.94 (s, 1H), 8.03 (d, J=5.2 Hz, 1H),7.87 (s, 1H), 7.79-7.75 (m, 2H), 7.51 (d, J=8.0 Hz, 1H), 6.95 (bs, 1H),6.56-6.52 (m, 2H), 2.78 (s, 3H), 2.42 (s, 3H); MS m/z 485.0 (M+H)⁺.

Example 208:N-{2-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-3-methoxy-phenyl}-2,2-dimethyl-propionamide

To a stirred solution of N-(3-methoxy-phenyl)-2,2-dimethyl-propionamide(1.11 g, 4.8 mmol) in anhydrous THF at 0° C. was added a solution ofn-BuLi (3.65 mL, 9.1 mmol) in hexanes. After 45 minutes, anhydrousMgBr₂-Et₂₀ (1.23 g, 4.8 mmol) was added in one portion and stirring wascontinued at the same temperature for 1 h. The mixture was then cooledto −78° C. and solid4-chloro-N-(5-chloro-2-formyl-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide(300 mg, 0.75 mmol) was added in one portion and slowly warmed to roomtemperature over 4 h. The mixture was then quenched with saturatedaqueous NH₄Cl (10 mL), and extracted with EtOAc (3×75 mL). The combinedextracts were washed with brine, dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel using ethyl acetate-hexane to provideN-(2-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-hydroxy-methyl}-3-methoxy-phenyl)-2,2-dimethyl-propionamide:MS m/z 606.0 (M+H)⁺.

A mixture ofN-(2-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-hydroxy-methyl}-3-methoxy-phenyl)-2,2-dimethyl-propionamide(0.17 g, 0.33 mmol) and Dess-Martin reagent (0.185 g, 0.44 mmol) inCH₂Cl₂ (10 mL) at room temperature was stirred for 5 h. A mixture of 10%aqueous Na₂S₂O₃ (10 mL) and saturated aqueous NaHCO₃ (10 mL) was thenadded and the biphasic mixture vigorously stirred for 30 min. Theorganic phase was then separated and the aqueous portion was extractedwith CH₂Cl₂. The combined organic extracts were washed with saturatedaqueous NaHCO₃ and brine, dried (Na₂SO₄), and filtered. The filtrate wasconcentrated under reduced pressure and the residue purified bychromatography on silica gel using ethyl acetate-hexane to provideN-{2-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-3-methoxy-phenyl}-2,2-dimethyl-propionamide:MS m/z 604.0 (M+H)⁺.

A solution ofN-{2-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-3-methoxy-phenyl}-2,2-dimethyl-propionamide(105 mg, 0.17 mmol) in AcOH (6 mL) and 2M aqueous HCl (1 mL) was heatedat 60° C. for 4 days. The reaction mixture was neutralized with aqueousNaHCO₃, extracted with EtOAc. The combined organic extracts were washedwith saturated aqueous NaHCO₃ and brine, dried (Na₂SO₄), and filtered.The filtrate was concentrated under reduced pressure and the residuepurified by HPLC to provideN-[2-(2-amino-6-methoxy-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide:MS m/z 520.0 (M+H)⁺.

Example 209:2-(2-Dimethylamino-vinylamino)-N-methoxy-N-methyl-isonicotinamide

A 250 mL round-bottom flask was charged with 2-amino-isonicotinic acid(3.98 g, 28.6 mmol), N,O-dimethyl hydroxylamine hydrochloride (4.21 g,42.9 mmol), triethylamine (11.6 g, 114.5 mmol), and dimethylformamide(57 mL). The mixture was cooled to 0° C., and then BOP (14.0 g, 31.5mmol) was added slowly. The resultant heterogeneous solution was allowedto stir overnight, during which the reaction warmed to ambienttemperature as the ice-bath melted. The following day, the reaction wasdiluted with EtOAc, the organics were washed with saturated sodiumbicarbonate, dried with sodium sulfate, concentrated in vacuo, andpurified via automated silica gel chromatography to afford the Weinrebamide.

To a solution of 2-amino-N-methoxy-N-methyl-isonicotinamide (2.80 g) inDMF (15 mL) was added DMF dimethylacetal (6.14 mL, 46.2 mmol). Thesolution was warmed to 100° C. and stirred overnight. The following day,the organics were removed in vacuo and the oily residue was partitionedwith EtOAc/saturated sodium bicarbonate. The aqueous layer was extractedwith EtOAc, dried with sodium sulfate, concentrated in vacuo, andpurified via automated silica gel chromatography to produce 3.21 g (88%)of 2-(2-dimethylamino-vinylamino)-N-methoxy-N-methyl-isonicotinamidecontaminated with a small quantity of HMPA.

Example 210: 2-Chloro-N-methoxy-N-methyl-nicotinamide

To a solution of 2-chloro-nicotinoyl chloride (7.00 g, 39.8 mmol) andsodium bicarbonate (10.0 g, 119 mmol) in 1:1 THF/H₂O (110 mL) at 0° C.was added N,O-dimethyl hydroxylamine hydrochloride (4.68 g, 47.7 mmol).The resultant solution was stirred 2 h at 0° C., neutralized with 10%HCl to pH ˜7, and the aqueous layer was extracted two times with EtOAc.The combined organics were dried with sodium sulfate and concentrated invacuo to produce 6.96 g (87%) of the crude nicotinamide, which was usedwithout further purification.

Example 211: Pyridine-2-carboxylic Acid methoxy-methyl-amide

Following the procedure for example 157, picolinoyl chloridehydrochloride (3.0 g, 16.9 mmol) was converted to pyridine-2-carboxylicacid methoxy-methyl-amide.

Example 212: 2-Chloro-N-methoxy-N-methyl-isonicotinamide

A 500 mL round-bottom flask was charged with 2-chloro isonicotinic acid(4.19 g, 26.5 mmol), N,O-dimethyl hydroxylamine hydrochloride (3.12 g,31.8 mmol), diisopropylethylamine (12.0 g, 92.7 mmol), and methylenechloride (130 mL). The mixture was cooled to 0° C., and thenpropylphosphonic anhydride (16.6 mL, 50% solution in EtOAc) was addedslowly. The resultant heterogeneous solution was allowed to stirovernight, during which the reaction warmed to ambient temperature asthe ice-bath melted. The following day, the reaction was diluted withEtOAc, the organics were washed with saturated sodium bicarbonate, driedwith sodium sulfate, concentrated in vacuo, and purified via automatedsilica gel chromatography to afford the Weinreb amide.

Example 213:2-[Bis-(4-methoxy-benzyl)-amino]-N-methoxy-N-methyl-isonicotinamide

A 40 mL vial was charged with2-chloro-N-methoxy-N-methyl-isonicotinamide (800 mg, 3.86 mmol),bis-(4-methoxy-benzyl)-amine (1.49 g, 5.80 mmol),1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene-(1,4-naphthoquinone)palladium(0) dimer (126 mg, 0.097 mmol), sodium tert-butoxide (519 mg, 5.41mmol), and dioxane (12 mL). The vial was sealed, warmed to 110° C., andstirred overnight. The next day, the reaction was filtered throughCelite, dry loaded onto silica gel, and purified via automated silicagel chromatography to generate 795 mg (47%) of the protectedaminopyridine.

Example 214: 6-Chloro-pyridine-2-carboxylic Acid methoxy-methyl-amide

A 250 mL round-bottom flask was charged with 6-chloro picolinic acid(4.00 g, 25.3 mmol), N,O-dimethyl hydroxylamine hydrochloride (2.73 g,27.8 mmol), triethylamine (8.44 g, 83.5 mmol), and dimethylformamide (50mL). The mixture was cooled to 0° C., and then BOP (11.8 g, 26.6 mmol)was added slowly. The resultant heterogenous solution was allowed tostir overnight, during which the reaction warmed to ambient temperatureas the ice-bath melted. The following day, the reaction was diluted withEtOAc, the organics were washed with saturated sodium bicarbonate, driedwith sodium sulfate, concentrated in vacuo, and purified via automatedsilica gel chromatography to afford the Weinreb amide.

Example 215: 2-Methanesulfonylamino-N-methoxy-N-methyl-isonicotinamide

2-Amino-N-methoxy-N-methyl-isonicotinamide (575 mg, 3.16 mmol) wasdissolved in pyridine (4 mL), followed by the addition ofmethanesulfonyl chloride (0.73 mL, 9.48 mmol). The reaction wassubsequently warmed to 40° C. and stirred 5 h. The resultant mixture wasquenched with 10% HCl, diluted with EtOAc, and the organic layer washedwith 10% HCl and saturated sodium bicarbonate. The combined organicswere dried with sodium sulfate, concentrated in vacuo, and purified viaautomated silica gel chromatography to produce the desired sulfonamide.

Example 216: 2-chloro-N-methoxy-3,N-dimethyl-benzamide

To a cooled mixture of 2-chloro-3-methyl-benzoic acid (1 g, 5.88 mmol),N,O-dimethylhydroxyl amine (860 mg, 8.82 mmol) and Et₃N (3.27 mL, 23.52mmol) in CH₂Cl₂ (10 mL) was added 1-propane phosphonic acid cyclicanhydride (4.49 mL, 7.05 mmol; 50 wt % solution in EtOAc) dropwise andstirred at room temperature for 3 h. The reaction mixture was filtered,washed with CH₂Cl₂ (2×10 mL), evaporated to dryness and subjected tocolumn chromatography (SiO₂, 40% EtOAc-hexanes) to obtain2-chloro-N-methoxy-3,N-dimethyl-benzamide (1.19 g) in 95% yield. ESMSm/z (relative intensity): 214 (M+H)⁺ (100).

Example 217: 2-chloro-N-methoxy-5,N-dimethyl-benzamide

To a cooled mixture of 2-chloro-5-methyl-benzoic acid (1 g, mmol),N,O-dimethylhydroxyl amine (860 mg, 8.82 mmol) and Et₃N (3.27 mL) inCH₂Cl₂ (10 mL) was added 1-propane phosphonic acid cyclic anhydride(4.49 mL, 7.05 mmol; 50 wt % solution in EtOAc) dropwise and stirred atroom temperature for 3 h. The reaction mixture was filtered, washed withCH₂Cl₂ (mL), evaporated to dryness and subjected to columnchromatography (SiO₂, 40% EtOAc-hexanes) to obtain2-chloro-N-methoxy-5,N-dimethyl-benzamide (1.19 g) as white crystallinesolid in 95% yield. ESMS m/z (relative intensity): 214.1 (M+H)⁺ (100).

Example 218: 2,N-dimethoxy-N-methyl-nicotinamide

To a cooled mixture of 2-methoxy-nicotinic acid (2 g, 13.05 mmol), N,O-dimethylhydroxyl amine (1.91 g, 19.59 mmol) in CH₂Cl₂ (20 mL) and Et₃N(7.26 mL, 15.66 mmol) was added 1-propane phosphonic acid cyclicanhydride (9.96 mL, 15.66 mmol; 50 wt % solution in EtOAc) dropwise andstirred at room temperature for 2 h. The reaction mixture was filtered,washed with CH₂Cl₂ (10 mL), evaporated to dryness and subjected tocolumn chromatography (SiO₂, 50% EtOAc-hexanes) to obtain2,N-dimethoxy-N-methyl-nicotinamide (2.33 g) in 91% yield.

Example 219:4-Chloro-N-[5-chloro-2-(2-chloro-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

4-Chloro-N-(5-chloro-2-iodo-pyridin-3-yl)-3-trifluoromethyl-benzenesulfonamide(250 mg, 0.503 mmol) was placed in a dry 2-neck 10 mL round-bottomflask. The flask was evacuated and purged with nitrogen, followed by theaddition of THF (1.7 mL). The homogeneous mixture was lowered to −5° C.and i-PrMgCl (0.60 mL, 2.0M) was added dropwise. Upon completion of theaddition, the reaction was stirred 45 minutes, followed by the additionof 2-chloro-N-methoxy-N-methyl-nicotinamide (201 mg, 1.01 mmol). Thehomogeneous mixture was stirred 70 min at −5° C., then overnight atambient temperature. The resultant solution was quenched with 10% HCland diluted with EtOAc. The organics were washed with 10% HCl andsaturated sodium bicarbonate, dried with sodium sulfate, concentrated invacuo, and purified via automated silica gel chromatography to affordthe diaryl ketone: MS (ES) (M+H)⁺ expected 509.9, found 509.8.

Example 220:4-Chloro-N-[5-chloro-2-(2,3-dichloro-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

2,3-Dichloropyridine (129 mg, 0.873 mmol) was placed in a dry 2-neck 10mL round-bottom flask. The flask was evacuated and purged with nitrogen,followed by the addition of THF (1.75 mL). The homogeneous mixture waslowered to −78° C. and nBuLi (0.35 mL, 2.5M) was added dropwise. Uponcompletion of the addition, the reaction was stirred for 90 minutes,followed by the addition of5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methoxy-methyl-amide (50 mg, 0.109 mmol). The homogeneous mixturewas stirred 60 min at −78° C., then warmed to room temperature andstirred an additional 6 h. The resultant solution was quenched with 10%HCl and diluted with EtOAc. The organics were washed with 10% HCl andsaturated sodium bicarbonate, dried with sodium sulfate, concentrated invacuo, and purified via automated silica gel chromatography to affordthe desired diaryl ketone: ¹H NMR (400 MHz, CDCl₃) δ 10.88 (bs, 1H),8.41 (d, 1H), 8.16-8.28 (m, 3H), 8.04 (d, 1H), 7.71 (d, 1H), 7.12 (d,1H); MS (ES) (M+H)⁺ expected 543.9, found 543.8.

Example 221:4-Chloro-N-[5-chloro-2-(3-chloro-2-hydroxy-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A 1 dram vial was charged with4-chloro-N-[5-chloro-2-(2,3-dichloro-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(15 mg, 0.028 mmol), formic acid (0.39 mL) and water (0.13 mL). Theheterogeneous solution was warmed to 100° C. and stirred overnight. Thefollowing day, starting material remained; therefore, an additional 0.26mL of formic acid was added. The reaction was subsequently warmed to110° C. and stirred overnight. The resultant mixture was neutralizedwith saturated aqueous sodium bicarbonate, diluted with EtOAc, and theorganic layer washed with saturated sodium bicarbonate. The combinedorganics were dried with sodium sulfate, concentrated in vacuo, andpurified via automated silica gel chromatography to afford the desiredhydroxypyridine: ¹H NMR (400 MHz, CD₃OD) δ 8.26-8.38 (m, 1H), 8.17-8.20(m, 2H), 8.02-8.07 (m, 1H), 7.72-7.76 (m, 1H), 7.34-7.37 (m, 1H),6.17-6.20 (m, 1H); MS (ES) [M+H]⁺ expected 525.9, found 525.9.

Example 222:4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(984 mg, 2.0 mmol) in THF (10 mL) under nitrogen atmosphere at 0° C. wasadded dropwise isopropylmagnesium chloride (2M solution in THF, 2.5 mL,5.0 mmol). The mixture was then stirred for 30 min at 0° C. followed bythe addition of 2-chloro-N-methoxy-3,N-dimethyl-benzamide (852 mg, 4.0mmol) at 0° C. The mixture was stirred at room temperature for 3 h,quenched with saturated aqueous NH₄Cl solution (5 mL), and extractedwith EtOAc (2×25 mL). The combined organic layers were washed withsaturated aqueous NH₄Cl solution (25 mL), brine (25 mL), dried(anhydrous Na₂SO₄) and concentrated under reduced pressure. The residuewas column purified (SiO₂, 50% EtOAc-hexanes) to obtain4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(586 mg) in 52% yield. ESMS m/z (relative intensity): 534.9 [(M−32+H)]⁺(70), 588.9 (M+Na)+.

Example 223:4-Chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(58.6 mg, 1.03 mmol) in 4N HCl in dioxane (4 mL) and water (1 mL) wasstirred at 100° C. for overnight. The reaction mixture was cooled toroom temperature, evaporated to dryness and treated with saturatedaqueous NaHCO₃ solution till pH 7-8. The mixture was extracted withEtOAc (2×25 mL), dried (anhydrous Na₂SO₄) and concentrated. The obtainedresidue was purified via column chromatography (SiO₂, 70% EtOAc inhexanes) to afford4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(34.5 mg) in 64% yield. ¹H NMR (400 MHz, CDCl₃) δ11.00 (s, 1H), 8.24 (d,1H), 8.18 (m, 1H), 8.17 (d, 1H), 7.98 (dd, 1H), 7.63 (d, 1H), 7.35 (d,1H), 7.24 (t, 1H), 7.1 (d, 1H), 2.37 (s, 3H); ESMS m/z (relativeintensity): 522.9 (M+H)⁺ (100), 544.9 (M+Na)⁺ (100).

Example 224:4-chloro-N-[5-chloro-2-(2-chloro-5-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(984 mg, 2.0 mmol) in THF (10 mL) under nitrogen atmosphere at 0° C. wasadded dropwise isopropylmagnesium chloride (2M solution in THF, 2.5 mL,5.0 mmol). The mixture was then stirred for 30 min at 0° C. followed bythe addition of 2-chloro-N-methoxy-5,N-dimethyl-benzamide (852 mg, 4.0mmol) at 0° C. The mixture was stirred at room temperature for 3 hours,quenched with saturated aqueous NH₄Cl solution (5 mL) and extracted withEtOAc (2×25 mL). The combined organic layers were washed with saturatedaqueous NH₄Cl solution (25 mL), brine (25 mL), dried (anhydrous Na₂SO₄),and concentrated under reduced pressure. The obtained residue waspurified via column chromatography (SiO₂, 50% EtOAc-hexanes) to obtain4-chloro-N-[5-chloro-2-(2-chloro-5-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(543 mg) in 48% yield. ESMS m/z (relative intensity): 534.9 [(M−32+H)]⁺(35), 588.9 (M+Na)⁺ (100).

Example 225:4-chloro-N-[5-chloro-2-(2-chloro-5-methyl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[5-chloro-2-(2-chloro-5-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(50 mg, 0.088 mmol) in 4N HCl in dioxane (4 mL) and water (1 mL) wasstirred at 100° C. for overnight. The reaction mixture was cooled toroom temperature, evaporated to dryness and treated with saturatedaqueous NaHCO₃ solution till pH 7-8. The mixture was extracted withEtOAc (2×25 mL), dried (anhydrous Na₂SO₄) and concentrated. The obtainedresidue was purified via column chromatography to afford4-chloro-N-[5-chloro-2-(2-chloro-5-methyl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (29.5 mg) in 64% yield. ESMS m/z (relative intensity): 522.9(M+H)⁺ (30), 544.9 (M+Na) (50).

Example 226:4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(612 mg, 1.24 mmol) in THF (5 mL) under nitrogen atmosphere at 0° C. wasadded dropwise isopropylmagnesium chloride (2M solution in THF, 1.55 mL,3.1 mmol). The mixture was then stirred for 30 min at 0° C. followed bythe addition of a solution of 2,N-dimethoxy-N-methyl-nicotinamide (487mg, 2.48 mmol) in THF (2 mL) at 0° C. The mixture was stirred at roomtemperature for 6 hours, quenched with saturated aqueous NH₄Cl solution(5 mL) and extracted with EtOAc (2×25 mL). The combined organic layerswere washed with saturated aqueous NH₄Cl solution (25 mL), brine (25mL), dried (anhydrous Na₂SO₄) and concentrated under reduced pressure.The obtained residue was purified via column chromatography (SiO₂, 50%EtOAc-hexanes) to obtain4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(200 mg) in 29.2% yield. ESMS m/z (relative intensity): 550 (M+H)⁺(100), 571.9 (M+Na)⁺ (80).

Example 227:4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(330.06 mg, mmol) in 5% H₂SO₄ in TFA (2 mL) and water (1 mL) was stirredat 50° C. for overnight. The reaction mixture was cooled to roomtemperature, diluted with water (5 mL) and treated slowly with saturatedaqueous NaHCO₃ solution till pH 7-8. The mixture was extracted withEtOAc (2×25 mL), dried (anhydrous Na₂SO₄) and concentrated. The obtainedresidue was purified via column chromatography (SiO₂, 5% MeOH in EtOAc)to afford4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (15 mg) in 50% yield. ESMS m/z (relative intensity): 505.9(M+H)⁺ (100), 527.9 (M+Na)⁺ (20).

Example 228:4-chloro-N-[5-chloro-2-(2-hydroxy-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (10 mg, mmol) in 30% HBr in AcOH (1 mL) was stirred at 50°C. for 2 h. The reaction mixture was cooled to room temperature, dilutedwith water (1 mL) and treated with saturated aqueous NaHCO₃ solutionslowly till pH 5-6. The mixture was extracted with EtOAc (2×25 mL),dried (anhydrous Na₂SO₄) and concentrated. The obtained residue wascolumn purified (SiO₂, 10% MeOH in CH₂Cl₂) to afford4-chloro-N-[5-chloro-2-(2-hydroxy-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(6 mg) in 61.8% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, 1H), 8.17 (d,1H), 8.15 (d, 1H), 7.97 (dd, 1H), 7.72 (dd, 1H), 7.63 (d, 1H), 7.43 (dd,1H), 6.37 (t, 1H); ESMS m/z (relative intensity): 491.9 (M+H)+(100).

Example 229:2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-4-iodo-pyridine

2-Fluoro-4-iodo-pyridine (607 mg, 2.72 mmol), ethylene glycol (760 uL,13.6 mmol) and 60% sodium hydride (120 mg, 2.99 mmol) were sequentiallyadded to 2 mL of anhydrous DMF at room temperature. The solution wasthen brought to 60° C. and stirred for 2 hours, then cooled down anddiluted with 20 mL of water. The mixture was extracted 2 times with 30mL of diethyl ether. The combined organic layers were washed with 10 mLof water, then 10 mL of brine and dried over anhydrous magnesiumsulfate. After concentrating the mixture under reduced pressure, theresidue was dissolved in 2 mL of anhydrous acetonitrile. To thissolution tert-butylchlorodimethylsilane (453 mg, 3.00 mmol) andtriethylamine (459

L, 3.30 mmol) were added and the mixture was stirred at r.t. for 3 daysfollowing evaporation under reduced pressure. The residue was taken upin 40 mL of a 1:1 mixture of diethyl ether and water. The organic layerwas concentrated under reduced pressure and the residue purified on a 40g silica column eluted with a gradient of 0-15% ethyl acetate in hexanesto yield 630 mg of the product as colorless oil. MS: (M+H)/z=380.0.

Example 230:4-Chloro-N-{5-chloro-2-[2-(2-hydroxy-ethoxy)-pyridine-4-carbonyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-4-iodo-pyridine (305 mg,0.805 mmol) was dissolved in 1 mL of dry THF. To this solutionisopropylmagnesium chloride solution (2M in THF, 0.44 mL, 0.88 mmol) wasadded at room temperature. After 30 minutes this solution was added to asolution of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid methoxy-methyl-amide (283 mg, 0.564 mmol) in 1 mL dry THF at −78°C. The mixture was allowed to warm up to room temperature and stirredovernight followed by addition of 5 mL of aqueous saturated ammoniumchloride and extraction with 15 mL DCM. The organic solution wasevaporated under reduced pressure and purified on a 4 g silica columneluted with a gradient of 10-40% ethyl acetate in hexanes to yield 205mg ofN-(2-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-pyridine-4-carbonyl}-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideas a colorless oil.

A solution ofN-(2-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-pyridine-4-carbonyl}-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidein 4N HCl in dioxane (4 mL) and water (1 mL) was stirred at 100° C. forovernight. The reaction mixture was cooled to room temperature,evaporated to dryness and treated with saturated aqueous NaHCO₃ solutiontill pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried(anhydrous Na₂SO₄) and concentrated. The crude product was purified byHPLC. ¹H NMR (400 MHz, CDCl₃) δ 10.82 (s, 1H), 8.35 (m, 1H), 8.24 (m,1H), 8.15-8.18 (m, 2H), 7.96 (m, 1H), 7.63 (m, 1H), 7.17 (m, 1H), 7.09(m, 1H), 4.51 (m, 2H), 3.97 (m, 2H), 3.09 (m, 1H); MS: (M+H)/z=535.9.

Example 231:(S)-4-Chloro-N-(5-chloro-2-(4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide

General Synthesis of Amides

A 10 mL scintillation vial was charged with5-chloro-3-(4-chloro-3-(trifluoromethyl)phenyl-sulfonamido)picolinicacid (164 mg, 0.4 mmol), freshly prepared 3,3-dimethylpiperidin-4-ol(0.56 mmol) ((M+H)+, 130.1), HATU (192 mg, 0.5 mmol), DIEA (260 mg, 2mmol) and anhydrous DMF (1.5 mL). The resultant solution was heated to70° C. and stirred for 2 h. After cooled to room temperature, themixture was purified via preparative HPLC and dried (lyophilizer) toafford the title compound (1:2 mixture of rotamers): ¹H NMR (400 MHz,CDCl₃) (major rotamer) δ 9.54 (s, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.00(d, 1H), 7.88 (dd, 1H), 7.62 (d, 1H), 4.05 (m, 1H), 3.70 (d, 1H), 3.50(m, 2H), 3.40 (m, 1H), 3.10 (d, 1H), 1.82 (m, 2H), 1.00 (s, 3H), 0.92(s, 3H); MS (ES) (M+H)⁺ expected 526.0, found 526.0.

Example 232:5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-N-methyl-N-(pyridin-3-yl)picolinamide

The title compound was prepared according to above method for example179: ¹H NMR (400 MHz, CDCl₃) δ 8.62 (dd, 1H), 8.52 (s, 1H), 8.22 (d,1H), 8.02 (dd, 1H), 7.96 (d, 1H), 7.80 (s, 1H), 7.68 (m, 3H), 3.50 (s,3H); MS (ES) (M+H)⁺ expected 505.0, found 505.0.

Example 233:4-Chloro-N-(5-chloro-2-(2-chloro-6-nitrobenzoyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-(trifluoromethyl)benzenesulfonamide(1.0 g, 2.0 mmol) was placed in a dry 100 mL round-bottom flask sealedwith septa. The flask was evacuated and purged with nitrogen, followedby the addition of dry THF (30 mL). The homogeneous solution was cooledto 0° C. and i-PrMgCl (3.0 mL, 2.0M) was added dropwise. Upon completionof the addition, the mixture was stirred at 0° C. for 60 min, followedby the slow addition of 2-chloro-6-nitrobenzaldehyde (930 mg, 5 mmol).The reaction mixture was stirred at 0° C. for 3 h. The reaction wasquenched with NH₄Cl (sat) and extracted with EtOAc, washed with brine,dried over MgSO₄, and concentrated under reduced pressure. The residuewas further purified through automated normal-phase chromatography toafford4-chloro-N-(5-chloro-2((2-chloro-6-nitrophenyl)(hydroxymethyl)pyridin-3-yl)-N-methoxymethyl-3-(trifluoromethyl)benzenesulfonamide(600 mg, 49%) (which was used directly for the next step).

Step 2

The above4-chloro-N-(5-chloro-2((2-chloro-6-nitrophenyl)-(hydroxymethyl)pyridin-3-yl)-N-methoxymethyl-3-(trifluoromethyl)-benzenesulfonamidewas dissolved in DCM (30 mL) and treated with Dess-Martin periodinane(2.4 g, 5 mmol) at room temperature for 3 h. After evaporation ofsolvent, the residue was treated with (4.0M HCl in dioxane) (10 mL, 40mmol) and H₂O (4 mL), and then stirred at 110° C. for 6 h. The mixturewas diluted with EtOAc. The resultant organics were washed with NaHCO₃(sat), and brine; dried (MgSO₄), and concentrated under reduced pressureand purified through automated normal-phase chromatography to afford thetitle compound: ¹H NMR (400 MHz, CDCl₃) δ 10.90 (s, 1H), 8.23 (m, 2H),8.16 (d, 1H), 8.08 (d, 1H), 7.96 (dd, 1H), 7.73 (d, 1H), 7.64 (d, 1H),7.56 (t, 1H); MS (ES) (M+Na)⁺ expected 575.9, found 575.9.

Example 234: N-(2-(2-Amino-6-chlorobenzoyl)5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide

A 50 mL round-bottom flask was charged with4-chloro-N-(5-chloro-2-(2-chloro-6-nitrobenzoyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide (350 mg, 0.63 mmol), iron powder (560 mg, 10 mmol) inacetic acid (30 mL) and stirred at room temperature for 2 h and then at50° C. for 30 min. After cooling, the reaction mixture was diluted withEtOAc, filtered through Celite and evaporated the solvent in vacuo. Theresidue was dissolved in EtOAc and washed with NaHCO₃ (sat), brine,dried over MgSO₄, and concentrated under reduced pressure and wasfurther purified through automated normal-phase chromatography to affordthe title compound: ¹H NMR (400 MHz, CDCl₃) δ 10.60 (s, 1H), 8.28 (d,1H), 8.20 (d, 1H), 8.16 (d, 1H), 7.96 (dd, 1H), 7.60 (d, 1H), 7.09 (t,1H), 6.64 (dd, 2H), 4.40 (bs, 2H); MS (ES) [M+H]⁺ expected 523.9, found523.9.

Example 235: 4-Chloro-N-(5-chloro-2-(5-chloro-6-(methylsulfonamido)benzoyl)pyridin-3-yl)-3-(trifluoromethyl) Benzenesulfonamide

N-(2-(2-Amino-6-chlorobenzoyl)5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide(52 mg, 0.1 mmol) in pyridine/1,4-dioxane (1:1, 4 mL) was treated withmethanesulfonyl chloride (100 mg) and then stirred at 60° C. for 2 h.After evaporation of solvent under reduced pressure, to the mixture wasadded THF (5 mL), followed by NaOH (2N, 2 mL) and stirred at roomtemperature for another 2 h. The mixture was taken up in EtOAc, washedwith 1N HCl, NaHCO₃ (sat), brine, dried over MgSO₄, and concentratedunder reduced pressure and was further purified through automatednormal-phase chromatography to afford the title compound: ¹H NMR (400MHz, CDCl₃) δ 10.70 (s, 1H), 8.25 (m, 3H), 8.01 (d, 1H), 7.68 (d, 1H),7.60 (d, 1H), 7.50 (t, 1H), 7.42 (t, 1H), 7.23 (m, 1H), 6.52 (s, 1H),2.88 (s, 3H); MS (ES) (M+H)⁺ expected 603.9, found 603.9.

Example 236:4-Chloro-N-(5-chloro-2-(5-chloro-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide

N-(2-(2-Amino-6-chlorobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide(26 mg, 0.05 mmol) in THF (2 mL) was treated with TMS-isocyanate (100mg) and AcOH (0.5 mL) and then stirred at 75° C. for 12 h. To themixture was added MeOH (0.5 mL), followed by NaOH (5N, 1 mL), and theresultant mixture stirred at 75° C. for another 2 h. To the mixture wasadded AcOH (0.5 mL), and the mixture was purified through HPLC and dried(lyophilizer) to afford the title compound: ¹H NMR (400 MHz, CDCl₃) δ8.82 (s, 2H), 8.34 (d, 1H), 8.14 (d, 1H), 7.90 (dd, 1H), 7.66 (d, 1H),7.46 (s, 1H), 7.16 (t, 1H), 6.90 (d, 2H), 6.81 (d, 1H), 6.14 (d, 1H); MS(ES) (M+H)⁺ expected 550.9, found 550.9.

Example 237: N-(2-(2-Amino-6-chlorobenzoyl)5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 234,4-chloro-N-(5-chloro-2-(2-chloro-5-nitrobenzoyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide (MS 575.9, (M+Na)⁺) afforded the title compound: ¹HNMR (400 MHz, CDCl₃) δ 10.84 (s, 1H), 8.28 (d, 1H), 8.20 (d, 1H), 8.16(d, 1H), 7.98 (dd, 1H), 7.62 (d, 1H), 7.09 (t, 1H), 6.70 (d, 1H), 6.58(d, 1H), 3.80 (s, 2H); MS (ES) (M+H)⁺ expected 523.9, found 523.9.

Example 238:4-Chloro-N-(5-chloro-2-(2-chloro-5-ureidobenzoyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide

N-(2-(2-Amino-5-chlorobenzoyl)5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide(26 mg, 0.05 mmol) in THF (2 mL) was treated with TMS-isocyanate (100mg) and AcOH (0.5 mL) and then stirred at room temperature for 2 h. MeOH(1 mL) was added to the mixture which was then purified through HPLC anddried (lyophilizer) to afford the title compound: ¹H NMR (400 MHz,CDCl₃) δ 10.96 (s, 1H), 8.23 (m, 3H), 8.00 (dd, 1H), 7.64 (dd, 1H), 7.36(m, 3H), 6.80 (d, 1H), 5.00 (br, 2H); MS (ES) (M+H)⁺ expected 568.9,found 568.9.

Example 239: 4-Chloro-N-(5-chloro-2-(2-chloro-5-(3-methylureido)benzoyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide

N-(2-(2-Amino-5-chlorobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide(26 mg, 0.05 mmol) in THF (2 mL) was treated with methyl isocyanate (75mg) and AcOH (0.5 mL) and then stirred at room temperature for 2 h. MeOH(1 mL) was added to the mixture which was purified through HPLC anddried (lyophilizer) to afford the title compound: ¹H NMR (400 MHz,CDCl₃) δ 10.90 (s, 1H), 8.22 (m, 3H), 8.01 (dd, 1H), 7.64 (d, 1H),7.23-7.38 (m, 3H), 6.58 (s, 1H), 2.82 (s, 3H); MS (ES) (M+H)⁺ expected582.9, found 582.9.

Example 240:4-Chloro-N-(5-chloro-2-(2-chloro-5-(3-isopropylureido)benzoyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide

N-(2-(2-Amino-5-chlorobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide(25 mg, 0.05 mmol) in THF (2 mL) was treated with isopropyl isocyanate(85 mg) and AcOH (0.5 mL) and then stirred at room temperature for 2 h.MeOH (1 mL) was added to the mixture which was purified through HPLC anddried (lyophilizer) to afford the title compound: ¹H NMR (400 MHz,CDCl₃) δ 10.92 (s, 1H), 8.20 (m, 3H), 7.99 (dd, 1H), 7.64 (d, 1H),7.23-7.38 (m, 3H), 6.90 (s, 1H), 3.92 (m, 1H), 1.09 (d, 6H); MS (ES)(M⁺+H) expected 611.0, found 611.0.

Example 241:4-Chloro-N-(5-chloro-2-(2-chloro-5-(33,-dimethylureido)benzoyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide

N-(2-(2-Amino-5-chlorobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide(26 mg, 0.05 mmol) in THF/pyridine (1:1, 4 mL) was treated with dimethylcarbamic chloride (75 mg) and then stirred at 60° C. for 2 h. Afterevaporation of solvent under reduced pressure, the mixture was added THF(5 mL), followed by NaOH (2N, 2 mL) and stirred at room temperature foranother 2 h. The mixture was in EtOAc and washed with 1N HCl, NaHCO₃(sat), brine, dried over MgSO₄, and concentrated under reduced pressure.The residue was purified through HPLC and dried (lyophilizer) to affordthe title compound: ¹H NMR (400 MHz, CDCl₃) δ 10.90 (s, 1H), 8.22 (m,3H), 8.01 (dd, 1H), 7.64 (d, 1H), 7.23-7.38 (m, 3H), 6.58 (s, 1H), 3.10(s, 3H), 2.80 (s, 3H); MS (ES) (M+H)⁺ expected 596.9, found 596.9.

Example 242: 4-Chloro-N-(5-chloro-2-(2-chloro-5-(methylsulfonamido)benzoyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 235,N-(2-(2-Amino-5-chlorobenzoyl)5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)-benzenesulfonamideafforded the title compound: ¹H NMR (400 MHz, CDCl₃) b 10.90 (s, 1H),8.23 (m, 3H), 8.01 (dd, 1H), 7.64 (d, 2H), 7.38 (d, 1H), 7.23 (m, 1H),7.16 (d, 1H), 6.50 (s, 1H), 3.02 (s, 3H); MS (ES) (M+H)⁺ expected 603.9,found 603.9.

Example 243:4-Chloro-N-(5-chloro-2-(2-methoxy-5-(3-methylureido)benzoyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 239,N-(2-(2-methoxy-5-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)-benzenesulfonamide(MS, 520.0, (M+H)⁺) afforded the title compound: ¹H NMR (400 MHz, CDCl₃)δ 10.82 (s, 1H), 8.23 (d, 1H), 8.16 (m, 2H), 7.96 (dd, 1H), 7.63 (d,1H), 7.38 (dd, 1H), 7.17 (d, 1H), 6.92 (d, 1H), 3.58 (s, 3H), 2.82 (s,3H); MS (ES) (M+H)⁺ expected 577.0, found 577.0.

Example 244:4-Chloro-N-(5-chloro-2-(5-(3-isopropylureido)-2-methoxybenzoyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 240,N-(2-(2-methoxy-5-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)-benzenesulfonamide(MS, 520.0, (M+H)+) afforded the title compound: ¹H NMR (400 MHz, CDCl₃)δ 10.82 (s, 1H), 8.23 (d, 1H), 8.16 (m, 2H), 7.96 (dd, 1H), 7.63 (d,1H), 7.38 (dd, 1H), 7.10 (d, 1H), 6.92 (d, 1H), 3.95 (hep, 1H), 3.58 (s,3H), 1.18 (d, 6H); MS (ES) (M⁺+H) expected 605.0, found 605.0.

Example 245: 4-Chloro-N-(5-chloro-2-(2-methoxy-5-(methylsulfonamido)benzoyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 235,N-(2-(2-methoxy-5-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)-benzenesulfonamide(MS, 520.0, (M+H)⁺) afforded the title compound: ¹H NMR (400 MHz, CDCl₃)δ 10.82 (s, 1H), 8.23 (d, 1H), 8.16 (m, 2H), 7.96 (dd, 1H), 7.63 (d,1H), 7.42 (dd, 1H), 7.18 (d, 1H), 6.92 (d, 1H), 6.25 (s, 1H), 3.58 (s,3H), 3.00 (s, 3H); MS (ES) (M+H)⁺ expected 597.9, found 597.9.

Example 246:N-(2-(3-Aminobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 234,N-(2-(3-nitrobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzene-sulfonamideafforded the title compound: ¹H NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H),8.40 (d, 1H), 8.18 (d, 1H), 8.04 (d, 1H), 7.82 (dd, 1H), 7.50 (dd, 1H),7.20 (m, 1H), 7.02 (m, 2H), 6.88 (m, 1H), 3.80 (s, 2H); MS (ES) (M+H)⁺expected 489.9, found 489.9.

Example 247: 4-Chloro-N-(5-chloro-2-(3-(methylsulfonamido)benzoyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 235,N-(2-(3-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide afforded the title compound: ¹H NMR (400 MHz, CDCl₃)δ 10.70 (s, 1H), 8.38 (d, 1H), 8.18 (d, 1H), 8.12 (d, 1H), 7.90 (dd,1H), 7.66 (d, 1H), 7.58 (m, 2H), 7.44 (m, 2H), 6.45 (s, 1H), 3.04 (s,3H); MS (ES) (M+H)⁺ expected 567.9, found 567.9.

Example 248:4-Chloro-N-(5-chloro-2-(3-(3-methylureido)benzoyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 239,N-(2-(3-Aminobenzoyl)-5-chloro-pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide afforded the title compound: ¹H NMR (400 MHz, CDCl₃)δ 10.90 (s, 1H), 8.20 (d, 2H), 8.12 (d, 1H), 7.96 (dd, 1H), 7.44 (dd,1H), 7.32 (d, 1H), 7.23 (d, 1H), 7.14 (d, 1H), 6.45 (s, 1H), 2.58 (s,3H); MS (ES) (M+H)⁺ expected 547.0, found 547.0.

Example 249:N-(5-Chloro-2-(3-(3-methylureido)benzoyl)pyridine-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 239,N-(2-(3-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide (MS, 470.0, (M+H)⁺) afforded the title compound: ¹HNMR (400 MHz, CDCl₃) δ 10.61 (s, 1H), 8.32 (d, 1H), 8.18 (d, 1H), 8.02(s, 1H), 7.82 (dd, 2H), 7.67 (d, 1H), 7.58 (d, 1H), 7.45 (d, 1H), 7.35(m, 2H), 6.70 (s, 1H), 2.85 (s, 3H), 2.48 (s, 3H); MS (ES) (M+H)⁺expected 527.0, found 527.0.

Example 250:N-(5-Chloro-2-(2-chloro-5-(3-methylureido)benzoyl)pyridine-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 239,N-(2-(2-chloro-5-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzene-sulfonamide(MS, 504.0, (M+H)⁺) afforded the title compound: ¹H NMR (400 MHz, CDCl₃)δ 10.90 (s, 1H), 8.20 (d, 2H), 8.12 (d, 1H), 7.96 (dd, 1H), 7.40 (m,3H), 6.40 (s, 1H), 2.83 (s, 3H), 2.58 (s, 3H); MS (ES) (M+H) expected561.0, found 561.0.

Example 251:N-(5-chloro-2-(2-chloro-5-(methylsulfonamido)benzoyl)pyridin-3-yl)-4-chloro-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 239,N-(2-(2-chloro-5-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide (MS, 504.0, (M+H)+) afforded the title compound: ¹HNMR (400 MHz, CDCl₃) δ 10.90 (s, 1H), 8.20 (d, 2H), 8.12 (d, 1H), 7.96(dd, 1H), 7.44 (dd, 1H), 7.32 (d, 1H), 7.23 (d, 1H), 7.14 (d, 1H), 6.45(s, 1H), 3.04 (s, 3H), 2.58 (s, 3H); MS (ES) (M+H)⁺ expected 582.0,found 582.0.

Example 252:N-(5-Chloro-2-(2-fluoro-5-(3-methylureido)benzoyl)pyridine-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 239,N-(2-(2-fluoro-5-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzene-sulfonamide(MS, 488.0, (M+H)⁺) afforded the title compound: ¹H NMR (400 MHz, CDCl₃)δ 10.70 (s, 1H), 8.24 (d, 1H), 8.18 (d, 1H), 8.08 (d, 1H), 7.90 (dd,1H), 7.52 (m, 1H), 7.40 (m, 2H), 7.00 (dd, 1H), 6.38 (s, 1H), 2.82 (s,3H) 2.50 (s, 3H); MS (ES) (M+H)⁺ expected 545.0, found 545.0.

Example 253:N-(5-Chloro-2-(2-fluoro-5-(3-isopropylureido)benzoyl)pyridine-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 240,N-(2-(2-fluoro-5-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzene-sulfonamide:(MS, 488.0, (M+H)+) afforded the title compound: ¹H NMR (400 MHz, CDCl₃)δ 10.70 (s, 1H), 8.24 (d, 1H), 8.18 (d, 1H), 8.08 (d, 1H), 7.90 (dd,1H), 7.52 (m, 1H), 7.40 (m, 2H), 7.00 (dd, 1H), 6.24 (s, 1H), 3.95 (hep,1H), 2.50 (s, 3H), 1.20 (d, 6H); MS (ES) (M+H)⁺ expected 573.0, found573.0.

Example 254:N-(5-Chloro-2-(2-methoxy-5-(3-methylureido)benzoyl)pyridine-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 239,N-(2-(2-methoxy-5-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzene-sulfonamide(MS, 500.0, (M+H)+) afforded the title compound: ¹H NMR (400 MHz, CDCl₃)δ 10.90 (s, 1H), 8.18 (d, 1H), 8.16 (d, 1H), 8.10 (d, 1H), 7.96 (dd,1H), 7.42 (d, 1H), 7.38 (dd, 1H), 7.17 (d, 1H), 6.90 (d, 1H), 3.58 (s,3H), 2.82 (s, 3H), 2.56 (s, 3H); MS (ES) (M+H)⁺ expected 557.0, found557.0.

Example 255: N-(5-Chloro-2-(5-(3-isopropylureido)-2-methoxybenzoyl)pyridine-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 239,N-(2-(2-methoxy-5-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzene-sulfonamide(MS, 500.0, (M+H)⁺) afforded the title compound: ¹H NMR (400 MHz, CDCl₃)δ 10.90 (s, 1H), 8.18 (d, 1H), 8.16 (d, 1H), 8.10 (d, 1H), 7.96 (dd,1H), 7.45 (d, 1H), 7.38 (dd, 1H), 7.14 (d, 1H), 6.92 (d, 1H), 3.98 (m,1H), 3.60 (s, 3H), 2.58 (s, 3H), 1.09 (d, 6H); MS (ES) [M+H]⁺ expected585.0, found 585.0.

Example 256: N-(5-chloro-2-(2-methoxy-5-(methylsulfonamido)benzoyl)pyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 235,N-(2-(2-methoxy-5-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide (MS, 500.0, (M+H)+) afforded the title compound: ¹HNMR (400 MHz, CDCl₃) δ 10.90 (s, 1H), 8.18 (d, 1H), 8.16 (d, 1H), 8.10(d, 1H), 7.96 (dd, 1H), 7.40 (m, 2H), 7.17 (d, 1H), 6.90 (d, 1H), 3.58(s, 3H), 3.00 (s, 3H), 2.56 (s, 3H); MS (ES) (M+H)⁺ expected 578.0,found 578.0.

Example 257:N-(5-Chloro-2-(2-methoxy-3-(3-methylureido)benzoyl)pyridine-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide

According to the procedure for example 239,N-(2-(2-methoxy-3-aminobenzoyl)-5-chloro-pyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzene-sulfonamide(MS, 500.0, (M+H)) afforded the title compound: ¹H NMR (400 MHz, CDCl₃)δ 11.00 (s, 1H), 8.22 (d, 1H), 8.15 (d, 1H), 8.10 (m, 1H), 7.96 (dd,1H), 7.44 (d, 1H), 7.10 (t, 1H), 6.80 (m, 2H), 3.56 (s, 3H), 2.84 (s,3H), 2.56 (s, 3H); MS (ES) (M+H)⁺ expected 557.0, found 557.0.

Example 258:4-Chloro-N-(5-chloro-2-(3-oxo-3,4-dihydro-2H-benzoyl[b][1,4]oxazine-8-carbonyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-(trifluoromethyl)benzenesulfonamide(0.5 g, 1.0 mmol) was placed in a dry 100 mL round-bottom flask sealedwith septa. The flask was evacuated and purged with nitrogen, followedby the addition of dry THF (30 mL). The homogeneous solution was cooledto 0° C. and iPrMgCl (1.25 mL, 2.0M) was added dropwisely. Uponcompletion of the addition, the mixture was stirred at 0° C. for 60 min,followed by the slow addition of benzo[b][1,4]oxazin-3(4H)-one Weinrebamide (208 mg, 1 mmol). The reaction mixture was stirred at 0° C. for 3h. The reaction was quenched with NH₄Cl (sat) and extracted with EtOAc,washed with brine, dried over MgSO₄, and concentrated under reducedpressure. The residue was further purified through automatednormal-phase chromatography to afford4-xhloro-N-(5-chloro-2-(3-oxo-3,4-dihydro-2H-benzoyl[b][1,4]oxazine-8-carbonyl)pyridin-3-yl)-N-(methoxylmethyl)-3-(trifluoromethyl)benzenesulfonamide(0.5 g, 85%) (which was used directly for the next step).

Step 2

The above4-chloro-N-(5-chloro-2-(3-oxo-3,4-dihydro-2H-benzoyl[b][1,4]oxazine-8-carbonyl)pyridin-3-yl)-N-(methoxylmethyl)-3-(trifluoromethyl)benzenesulfonamidewas treated with (4.0M HCl in dioxane) (10 mL, 40 mmol) and H₂O (4 mL),and then stirred at 110° C. for 6 h. The mixture was diluted with EtOAc.The resultant organics were washed with NaHCO₃ (sat), and brine; dried(MgSO₄), and concentrated under reduced pressure and was purifiedthrough automated normal-phase chromatography to afford the titlecompound: ¹H NMR (400 MHz, CDCl₃) δ 10.90 (s, 1H), 8.25 (d, 1H), 8.16(d, 2H), 7.96 (m, 2H), 7.63 (d, 1H), 7.08 (m, 1H), 6.92 (m, 2H), 4.38(s, 2H); MS (ES) [M+H]⁺ expected 546.0, found 546.0.

Example 259:4-Chloro-N-[5-chloro-2-(6-fluoro-2-oxo-2,3-dihydro-benzooxazole-7-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Step 1

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(198 mg) in THF (0.6 mL) stirring at 0° C. was added isopropylmagnesiumchloride (2M solution in THF, 0.44 mL) via dropwise addition. Themixture was then stirred for 30 min at 0° C. followed by the addition of6-fluoro-2-oxo-2,3-dihydro-benzooxazole-7-carbaldehyde (Javier et. al.,Heterocycles, 1999, 1563.) (35 mg). The mixture was warmed to roomtemperature, stirred an additional 30 min and quenched by saturatedaqueous NH₄Cl solution (1 mL). The organic layer was separated and theaqueous layer was extracted by EtOAc (2×1 mL). The combined organiclayers were dried (Na₂SO₄), filtered and evaporated in vacuo. Theresidue was used directly in the next step.

Step 2

The residue from the last step was dissolved in CH₂Cl₂ (1 mL) andDess-Martin periodinane (127 mg) was added. The mixture was stirred atroom temperature for 12 h and was concentrated in vacuo. The residue waspurified by flash chromatography (silica) to afford4-chloro-N-{5-chloro-2-[(6-fluoro-2-oxo-2,3-dihydro-benzooxazol-7-yl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamideas a pale yellow solid.

Step 3

The yellow solid from last step was dissolved in a mixture of H₂O (6 mL)and HCl in dioxane (4M, 3 mL) and heated to 100° C. for 12 h. Themixture was cooled to room temperature and concentrated in vacuo. Theresidue was dissolved in EtOAc (10 mL) and washed by saturated aqueousNaHCO₃ solution (2 mL). The organic layer was separated and evaporatedin vacuo. The residue was purified by flash chromatography (silica) toafford the title compound as a white powder. MS (M+H)⁺: 549.9.

Example 260:N-[5-Chloro-2-(6-fluoro-2-oxo-2,3-dihydro-benzooxazole-7-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 259.MS (M+H)⁺: 530.0.

Example 261:4-Chloro-N-[5-chloro-2-(6-fluoro-2-oxo-2,3-dihydro-benzooxazole-7-carbonyl)-pyridin-3-yl]-3-methyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 259.MS (M+H)⁺: 495.9.

Example 262:4-Chloro-N-[5-chloro-2-(6-chloro-2-oxo-2,3-dihydro-benzooxazole-7-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 259.MS (M+H)⁺: 565.9.

Example 263:N-[5-Chloro-2-(6-chloro-2-oxo-2,3-dihydro-benzooxazole-7-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 259.MS (M+H)⁺: 546.0

Example 264:N-[5-Chloro-2-(6-fluoro-2-oxo-2,3-dihydro-benzooxazole-7-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 259.MS (M+H)⁺: 546.0.

Example 265:4-Chloro-N-[5-chloro-2-(2-oxo-2,3-dihydro-benzooxazole-7-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 259.MS (M+H)⁺: 531.9.

Example 266:N-[5-Chloro-2-(2-oxo-2,3-dihydro-benzooxazole-7-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 259.MS (M+H)⁺: 512.0.

Example 267:N-{5-Chloro-2-[hydroxy-(2-oxo-2,3-dihydro-benzooxazol-7-yl)-methyl]-pyridin-3-yl}-4-methyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-[5-chloro-2-(2-oxo-2,3-dihydro-benzooxazole-7-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide(41 mg) in THF (1 mL) and H₂O (0.1 mL) was added NaBH₄ (10 mg). Themixture was stirred at room temperature for 1 h, diluted by EtOAc (3 mL)and quenched by saturated aqueous NH₄Cl solution (1 mL). The organiclayer was separated, dried (Na₂SO₄), filtered and evaporated in vacuo.The residue was purified by flash chromatography (silica) to afford thetitle compound as a white powder. MS (M+H)⁺: 514.0.

Example 268:4-Chloro-N-[5-chloro-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

To a solution of 4-iodo-7-azaindazole (Potashman et. al., WO2005070891)(123 mg) in THF (2 mL) at 0° C. was added isopropylmagnesium chloride(2M solution in THF, 0.5 mL). The mixture was stirred at 0° C. for 30min and5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methoxy-methyl-amide (114 mg) was added. The reaction mixture waswarmed to room temperature, stirred for 2 h and quench by saturatedaqueous NH₄Cl solution (2 mL). The organic layer was separated and theaqueous layer was extracted with EtOAc (5 mL). The combined organiclayers were dried (Na₂SO₄), filtered and evaporated in vacuo. Theresidue was purified by flash chromatography (silica) to afford thetitle compound as a white powder. MS (M+H)⁺: 515.9.

Example 269:N-[5-Chloro-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 268.MS (M+H)⁺: 496.0.

Example 270:4-Chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 268using 4-iodo-7-azaindole (Kania et. al, WO2001002369) MS (M+H)⁺: 496.0.

Example 271:N-[5-Chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 271.MS (M+H)⁺: 495.0.

Example 272:4-Chloro-N-[5-chloro-2-(1H-indazole-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Step 1

To a solution of 1H-Indazole-4-carboxylic acid (Fletcher et. al.,WO2005028445) (480 mg), N, O-dimethylhydroxyamine hydrochloride salt(585 mg) and Et₃N (6 mL) in THF (15 mL) stirring at 0° C. was added T₃P(50% in EtOAc, 3 mL). The mixture was stirred at 0° C. for 1 h, dilutedby EtOAc (40 mL) and quenched by saturated aqueous NaHCO₃ solution (15mL). The organic layer was separated, dried (Na₂SO₄), filtered andevaporated in the vacuo to give a yellow liquid which was used as itwas.

Step 2

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(247 mg) in THF (1 mL) stirring at 0° C. was added isopropylmagnesiumchloride (2M solution in THF, 0.55 mL) via dropwise addition. Themixture was then stirred for 30 min at 0° C. followed by the addition of1H-indazole-4-carboxylic acid methoxy-methyl-amide (50 mg in 1 mL THF)obtained from step 1. The mixture was stirred at room temperature for 1h and quenched by saturated aqueous NH₄Cl solution (2 mL). The organiclayer was separated and the aqueous layer was extracted by EtOAc (2×3mL). The combined organic layer was dried (Na₂SO₄), filtered andevaporated in vacuo. The residue was purified by flash chromatography togive a yellow solid.

Step 3

The yellow solid obtained from step 2 was dissolved in a solution of HClin dioxane (4M, 4 mL) and H₂O (4 mL) and heated to 80° C. for 12 h. Themixture was cooled to room temperature and evaporated in vacuo. Theresidue was dissolved in EtOAc (10 mL) and washed by saturated aqueousNaHCO₃ solution (2 mL). The organic layer was separated and evaporatedin vacuo. The residue was was purified by flash chromatography (silica)to afford the title compound as a white powder. MS (M+H)⁺: 515.0.

Example 273:4-Chloro-N-{5-chloro-2-[methoxyimino-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

A solution of4-chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(41 mg), methoxylamine hydrochloride salt (67 mg) and Et₃N (0.14 mL) inTHF (1 mL) was heated to 80° C. for 12 h. The mixture was cooled to roomtemperature, diluted with EtOAc (5 mL), filtered and evaporated invacuo. The residue was purified by flash chromatography (silica) toafford the title compound as a white powder. MS (M+H)⁺: 544.0.

Example 274:N-{5-Chloro-2-[methoxyimino-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-pyridin-3-yl}-4-methyl-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 273.MS (M+H)⁺: 524.0.

Example 275:N-{5-Chloro-2-[hydroxyimino-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-pyridin-3-yl}-4-methyl-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 273.MS (M+H)⁺: 524.0.

Example 276:N-{5-Chloro-2-[ethoxyimino-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-pyridin-3-yl}-4-methyl-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 273.MS (M+H)⁺: 538.0.

Example 277:N-{5-Chloro-2-[isopropoxyimino-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-pyridin-3-yl}-4-methyl-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 273.MS (M+H)⁺: 552.0.

Example 278:[[5-Chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridin-2-yl]-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methyleneaminooxy]-aceticAcid

The title compound was synthesized in a manner similar to example 273.MS (M+H)⁺: 568.0.

Example 279:N-{2-[(2-Amino-pyridin-4-yl)-methoxyimino-methyl]-5-chloro-pyridin-3-yl}-4-chloro-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 273.MS (M+H)⁺: 519.9.

Example 280:N-{2-[(2-Amino-pyridin-4-yl)-methoxyimino-methyl]-5-chloro-pyridin-3-yl}-4-methyl-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized in a manner similar to example 273.MS (M+H)⁺: 500.0.

Example 281:4-Chloro-N-[5-chloro-2-(7-oxy-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(26 mg) and peracetic acid (32% wt in HOAc, 0.2 mL) was stirred at roomtemperature for 12 h. The mixture was loaded on reverse phase HPLC toafford the title compound as a pale yellow powder. MS (M+H)⁺: 530.9.

Example 282:4-Chloro-N-{5-chloro-2-[(2-hydroxy-pyridin-4-yl)-methoxyimino-methyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

The title compound was prepared by procedure analogous to that describedin Example 273 using4-chloro-N-[5-chloro-2-(2-hydroxy-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide.Purification on prep-HPLC (20-95% acetonitrile, 75 min) gave twoisomers, the minor being the one eluting first: Major isomer: ¹H NMR(400 MHz, CDCl₃) δ□10.82 (s, 1H), 8.20 (m, 1H), 8.17 (m, 1H), 8.01 (m,1H), 7.93 (m, 1H), 7.67 (m, 1H), 7.33 (m, 1H), 6.26 (s, 1H), 5.84 (m,1H), 4.14 (s, 3H) MS: (M+H)/z=521.0. Minor isomer: ¹H NMR (400 MHz,CDCl₃) δ 8.50 (m, 1H), 8.10 (m, 1H), 7.97 (m, 1H), 7.60 (m, 1H), 7.47(m, 1H), 7.16 (m, 1H), 6.50 (m, 1H), 5.48 (s, 1H), 4.10 (s, 3H) MS:(M+H)/z=521.0.

Example 283: 2-Chloro-3-[5-chloro-3-(4-chloro-3-trifluoromethylbenzenesulfonylamino)-pyridine-2-carbonyl] Benzoic Acid

To an oven-dried vial containingN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethylbenzenesulfonamide (316 mg, 0.64 mmol) was added anhydrous THF (2 mL)under positive nitrogen pressure. The vial was cooled to −40° C. (dryice-MeCN) and a 2.0M solution of i-PrMgCl in THF (0.80 mL, 1.6 mmol) wasadded. After 5 min, the solution was warmed to 0° C. After a further 30min, 2-chloro-N,N′-dimethoxy-N,N′-dimethyl-isophthalamide (320 mg, 1.11mmol) was added, and the reaction mixture was warmed to room temperatureover 1 h. The solution was maintained at room temperature for 24 h,after which time it was treated with saturated aqueous NH₄Cl (10 mL),and poured into EtOAc (50 mL). The organic phase was washed withsaturated aqueous NaCl (2×25 mL) and dried over MgSO₄. The volatileswere removed in vacuo, and the residue purified by flash chromatographyon 15 g of silica gel (0-75% EtOAc-Hexanes). To the resulting productwere added a 4.0N solution of HCl in dioxane (2.0 mL, 8.0 mmol) and H₂O(0.5 mL). The reaction mixture was heated to 80° C. for 2 h, then cooledto room temperature. The volatiles were removed in vacuo. The productwas purified by preparative HPLC (20→95% gradient of MeCN—H₂O with 0.1%TFA) and the pure fractions lyophilized to afford the title compound (44mg, 12% yield): HPLC retention time=2.76 minutes. MS (ES) [M−H]⁻expected 551.0, found 550.9. ¹H NMR (400 MHz, CDCl₃) δ 11.00 (s, 1H),8.18-8.21 (m, 3H), 8.08 (dd, J=2.0, 7.6 Hz, 1H), 8.01 (dd, J=2.4, 8.4Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.40-7.48 (m, 2H).

Example 284: 2-Chloro-3-[5-chloro-3-(4-chloro-3-trifluoromethylbenzenesulfonylamino)-pyridine-2-carbonyl]-N,N-dimethyl-benzamide

To a vial containing2-chloro-3-[5-chloro-3-(4-chloro-3-trifluoromethylbenzenesulfonylamino)-pyridine-2-carbonyl] benzoic acid (24 mg, 0.04 mmol) were addedHATU (19 mg, 0.05 mmol), DMF (0.5 mL), a 2.0M solution of Me₂NH in THF(40 μL, 0.08 mmol), and (i-Pr)₂NEt (10 μL, 0.06 mmol). The solution wasmaintained at room temperature for 5 h. EtOAc (10 mL) was added, and theorganic phase washed with saturated aqueous NaCl (1×5 mL), 0.1N aceticacid in water (1×5 mL), and dried over MgSO₄. The volatiles were removedin vacuo, and the resulting residue was purified by preparative HPLC(20→95% gradient of MeCN—H₂O with 0.1% TFA) and the pure fractionslyophilized to afford the title compound (5 mg, 22% yield): HPLCretention time=2.90 minutes. MS (ES) [M+H]⁺ expected 580.0, found 579.9.¹H NMR (400 MHz, CDCl₃) δ 10.94 (s, 1H), 8.17-8.20 (m, 3H), 7.98 (dd,J=2.4, 8.4 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.41 (d, J=4.4 Hz, 1H),7.28-7.30 (m, 2H), 3.12 (s, 3H), 2.86 (s, 3H).

Example 285:4-Chloro-N-[5-chloro-2-(8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)-pyridin-3-yl]-3-trifluoromethylbenzenesulfonamide.and4-chloro-N-[5-chloro-2-(5-chloro-4-oxo-3,4-dihydro-phthalazin-1-yl)-pyridin-3-yl]-3-trifluoromethylbenzenesulfonamide

To an oven-dried vial containingN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethylbenzene-sulfonamide(500 mg, 1.02 mmol) was added anhydrous THF (2 mL) under positivenitrogen pressure. The vial was cooled to −40° C. (dry ice-MeCN) and a2.0M solution of i-PrMgCl in THF (1.07 mL, 2.14 mmol) was added. After 5min, the solution was warmed to 0° C. After a further 30 min,3-chlorophthalic anhydride (173 mg, 0.95 mmol) was added, and thereaction mixture was warmed to room temperature over 1 h. The solutionwas maintained at room temperature for 24 h, after which time it wastreated with 1.0N NaHSO₄ (1 mL), and poured into EtOAc (100 mL). Theorganic phase was washed with saturated aqueous NaCl (2×25 mL) and driedover MgSO₄. The volatiles were removed in vacuo, and the resultingresidue purified by flash chromatography on 15 g of silica gel (0→20%MeOH—CHCl₃ with 0.5% formic acid) to give a 1:1 mixture of3-chloro-2-{5-chloro-3-[(4-chloro-3-trifluoromethylbenzenesulfonyl)methoxymethyl-amino]pyridine-2-carbonyl}benzoic acid and2-chloro-6-{5-chloro-3-[(4-chloro-3-trifluoromethylbenzenesulfonyl)methoxymethylamino]pyridine-2-carbonyl}benzoic acid (292 mg, 52% yield).

To the preceding mixture of carboxylic acids was added TFA (3 mL), H₂O,(0.6 mL), and conc. H₂SO₄ (20 μL) at 5° C. After 24 h at thistemperature, the reaction mixture was diluted with EtOAc (50 mL), washedwith water (1×25 mL), and dried over MgSO₄. The volatiles were removedin vacuo to afford a brown oil. EtOH (2 mL) and anhydrous hydrazine (0.1mL, 3.2 mmol) were added, and the solution heated to reflux. After 1 h,the reaction mixture was cooled to room temperature and diluted withEtOAc (50 mL). The organic phase was washed with 0.1N aqueous HOAc (3×10mL), dried over MgSO₄, and concentrated in vacuo to afford a brown oil.Purification by flash chromatography on 12 g of silica gel (0→75%EtOAc-Hexanes) afforded4-chloro-N-[5-chloro-2-(8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)-pyridin-3-yl]-3-trifluoromethylbenzenesulfonamide(15 mg, 6% yield): HPLC retention time=2.71 minutes. MS (ES) [M+H]⁺expected 549.0, found 548.9. ¹H NMR (400 MHz, CDCl₃) δ 11.03 (s, 1H),8.40-8.41 (m, 1H), 8.32-8.34 (m, 1H), 8.12-8.13 (m, 1H), 7.96 (bs, 1H),7.42-7.63 (m, 1H), 7.63-7.70 (m, 3H), 7.33-7.36 (m, 1H); and4-chloro-N-[5-chloro-2-(5-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)pyridin-3-yl]-3-trifluoromethylbenzenesulfonamide(12 mg, 4% yield): HPLC retention time=2.74 minutes. MS (ES) [M+H]⁺expected 549.0, found 548.9. ¹H NMR (400 MHz, CDCl₃) δ 10.74 (s, 1H),8.55 (d, J=2.4 Hz, 1H), 8.14 (d, J=2.4 Hz, 1H), 7.77 (dd, J=1.2, 8.0 Hz,1H), 7.71 (d, J=2 Hz, 1H), 7.76-7.59 (m, 1H), 7.53 (d, J=8 Hz, 1H), 7.45(dd, J=1.2, 8.0 Hz, 1H), 7.19-7.24 (m, 2H).

Example 286:2-Chloro-3-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-N-methyl-benzamide

To a vial containing2-chloro-3-[5-chloro-3-(4-chloro-3-trifluoromethylbenzene-sulfonylamino)-pyridine-2-carbonyl]benzoic acid (24 mg, 0.04 mmol) were added HATU (75 mg, 0.2 mmol), DMF(1 mL), a 2.0M solution of MeNH₂ in THF (0.3 mL, 0.6 mmol), and(i-Pr)₂NEt (35

L, 0.2 mmol). The solution was maintained at room temperature for 15 h.EtOAc (20 mL) was added, and the organic phase washed with saturatedaqueous NaCl (2×10 mL) and dried over MgSO₄. The volatiles were removedin vacuo, and the resulting residue was purified by preparative HPLC(20→95% gradient of MeCN—H₂O with 0.1% TFA). The pure fractions werelyophilized to afford the title compound (5 mg, 5% yield): HPLCretention time=2.69 minutes. MS (ES) [M+H]⁺ expected 566.0, found 565.9.¹H NMR (400 MHz, CDCl₃) δ 10.98 (s, 1H), 8.17-8.21 (m, 3H), 8.00 (dd,J=2.4, 8.8 Hz, 1H), 7.65-7.69 (m, 2H), 7.41 (t, J=7.2 Hz, 1H), 7.30 (dd,J=1.6, 7.2 Hz, 1H), 6.01 (bs, 1H), 3.01 (d, J=5.2 Hz, 3H).

Example 287:4-Chloro-N-[5-chloro-2-(3-(±)-hydroxypyrrolidine-1-carbonyl)pyridin-3-yl]-3-trifluoromethylbenzenesulfonamide

To a vial containing 5-chloro-3-(4-chloro-3-trifluoromethylbenzenesulfonylamino)-pyridine-2-carboxylic acid (20 mg, 0.05 mmol) wereadded 3-(±)-pyrrolidinol hydrochloride (13 mg, 0.11 mmol), BOP (25 mg,0.06 mmol), DMF (0.3 mL) and NEt₃ (40 μL, 0.29 mmol). The solution wasmaintained at room temperature for 24 h, then diluted with EtOAc (30mL), washed with saturated aqueous NaCl (3×5 mL), and dried over MgSO₄.The volatiles were removed in vacuo. The resulting residue was purifiedby preparative HPLC (20→95% gradient of MeCN—H₂O with 0.1% TFA) and thepure fractions lyophilized to afford the title compound (10 mg, 43%yield): HPLC retention time=2.49 minutes. MS (ES) [M+H]⁺ expected 484.0,found 484.0. ¹H NMR (400 MHz, CDCl₃) δ 11.38 (s, 1H), 8.21-8.24 (m, 1H),8.11-8.13 (m, 1H), 8.02-8.04 (m, 1H), 7.91-7.93 (m, 1H), 7.60-7.62 (m,1H), 4.50-4.53 (m, 1H), 3.82-4.01 (m, 2H), 3.65-3.76 (m, 3H), 1.95-2.04(m, 2H).

Example 288:N-{5-chloro-2-[2-chloro-3-(3-methylureido)benzoyl]pyridin-3-yl}-4-methyl-3-trifluoromethylbenzenesulfonamide

To an oven-dried vial containingN-(2-bromo-5-chloropyridin-3-yl)-N-methoxymethyl-4-methyl-3-trifluoromethylbenzenesulfonamide(1.00 g, 2.1 mmol) was added anhydrous THF (4 mL) under positivenitrogen pressure. The vial was cooled to −40° C. (dry ice-MeCN) and a2.0M solution of i-PrMgCl in THF (2.2 mL, 4.4 mmol) was added. After 5min, the solution was warmed to 0° C. After a further 30 min,2-chloro-3-nitrobenzaldehyde (600 mg, 3.2 mmol) was added, and thereaction mixture was warmed to room temperature over 1 h. The solutionwas maintained at room temperature for 48 h, after which time it waspoured into EtOAc (50 mL). The organic phase was washed with 0.1N HCl(1×25 mL), saturated aqueous NaCl (2×25 mL), and dried over MgSO₄. Thevolatiles were removed in vacuo to afford a brown oil that was usedwithout further purification.

The preceding oil was dissolved in CH₂Cl₂ (2 mL) and treated with a 15wt % solution of Dess-Martin Periodinane in CH₂Cl₂ (6 mL, 2.1 mmol).After 18 h, the reaction mixture was diluted with EtOAc (50 mL) andwashed with saturated aqueous NaCl (1×25 mL) and 10% aqueous NaHCO₃(1×25 mL). The organic phase was dried over MgSO₄, and concentrated invacuo to afford a brown oil. Purification by flash chromatography on 12g of silica gel (0→33% EtOAc-Hexanes) affordedN-[5-chloro-2-(2-chloro-3-nitrobenzoyl)pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethylbenzene-sulfonamide (490 mg, 40% yield over two steps). HPLC retentiontime=3.10 minutes. MS (ES) [M+Na]⁺ expected 600.0, found 599.9. ¹H NMR(400 MHz, CDCl₃) δ 8.52 (d, J=2.0 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.86(dd, J=1.6, 7.6 Hz, 1H), 7.75 (dd, J=2.0, 8.0 Hz, 1H), 7.64 (d, J=2.0Hz, 1H), 7.54 (dd, J=1.6, 7.6 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.38 (d,J=8.0 Hz, 1H), 5.31 (s, 2H), 3.41 (s, 3H), 2.53 (s, 3H).

To a vial containing a magnetic stir bar andN-[5-chloro-2-(2-chloro-3-nitro-benzoyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethylbenzenesulfonamide(100 mg, 0.17 mmol) was added EtOAc (0.5 mL). SnCl₂.2H₂O (240 mg, 1.06mmol) was added, and the mixture heated to 40° C. with vigorousstirring. After 1 h, the mixture was diluted with Et₂O (30 mL) andtreated with KF (120 mg, 2.07 mmol) and H₂O (3 mL). After stirring for 1h, the organic phase was filtered through Celite and concentrated invacuo to afford a yellow oil which was used without furtherpurification.

To the preceding oil were added a 4.0N solution of HCl in dioxane (4 mL,16 mmol), and H₂O (2 mL). The solution was heated to 40° C. for 18 h.After cooling to room temperature, the mixture was partitioned betweenEtOAc (30 mL) and a 1.0M solution of Na₂HPO₄ (10 mL). The organic phasewas washed with saturated aqueous NaCl (1×10 mL) and dried over MgSO₄.The volatiles were removed in vacuo, and the crude product used withoutfurther purification.

The preceding product was dissolved in CH₂Cl₂ (0.1 mL) and treated withmethyl isocyanate (20 μL, 0.34 mmol). After 6 h, the reaction mixturewas diluted with EtOAc (5 mL) and treated with saturated aqueous NaHCO₃(1 mL). The organic phase was dried over MgSO₄ and concentrated invacuo. The resulting product was purified by flash chromatography on 4 gof silica gel (20→100% EtOAc-Hexanes) to afford the title compound (20mg, 21% yield over 3 steps): HPLC retention time=2.75 minutes. MS (ES)[M+H]⁺ expected 561.0, found 560.9. ¹H NMR (400 MHz, CDCl₃) δ 10.97 (s,1H), 8.51 (d, J=2.0 Hz, 1H), 8.26 (dd, J=0.8, 8.0 Hz, 1H), 8.10-8.12 (m,1H), 7.96 (dd, J=2.0, 8.0 Hz, 1H), 7.71 (dd, J=1.4, 7.8 Hz, 1H), 7.67(d, J=2.0 Hz, 1H), 7.17-7.32 (m, 2H), 6.89 (bs, 1H), 6.76 (bs, 1H), 2.87(bs, 3H), 2.54 (s, 3H).

Example 289: 8-Formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic Acidtert-butyl Ester

To a suspension of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylicacid (1.51 g, 7.8 mmol) in anhydrous THF (10 mL) was added BH₃.Me₂S (2Min THF, 10 mL, 20 mmol) dropwise under nitrogen at 0° C. The resultedmixture was allowed to rise to r.t., and the reaction was continued tobe carried out at this temperature overnight. Then, saturated aqueousNH₄Cl (30 mL) was added in, and the resulted mixture was extracted withEtOAc (200 mL×2). The combined organic layers were washed with saturatedaqueous NaHCO₃ solution (30 mL), brine (30 mL), dried (Na₂SO₄) andfiltered before it was concentrated under reduced pressure. The resultedcrude product (3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-methanol, which wasutilized in the following step without further purification. MS m/z:166.2 (M+H)⁺.

To a suspension of (3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-methanol (1.49g, 7.8 mmol) in dioxane (10 mL) was added Et₃N (1 mL), and Boc₂O (3.41g, 15.6 mmol), the resulted mixture was stirred at r.t. for 2 h. Then,saturated aqueous NaHCO₃ (30 mL) was added in, and the resulted mixturewas extracted with EtOAc (150 mL×2). The combined organic layers werewashed with brine (30 mL), dried (Na₂SO₄) and filtered before it wasconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel to provide8-hydroxymethyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acidtert-butyl ester (1.11 g) as a white solid. ESMS m/z: 288.1 (M+Na)+.

To a solution of8-hydroxymethyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acidtert-butyl ester (591.2 mg, 2.2 mmol) in dioxane (4 mL) was addedpreactivated MnO₂ (2.00 g, 22.3 mmol), and the resulted mixture washeated at 80° C. for overnight. The resulted mixture was then cooled tor.t., and filtered. The solid was washed with EtOAc (20 mL×3). EtOAcwashing solution was combined with dioxane filtrate, and concentratedunder reduced pressure. The residue was purified by flash columnchromatography on silica gel to provide8-formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butylester (491.5 mg) as a white solid. MS m/z: 286.0 (M+Na)+.

Example 290:4-Chloro-N-[5-chloro-2-(3,4-dihydro-2H-benzo[1,4]oxazine-8-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(2.92 g, 6.18 mmol) in THF (12 mL) under nitrogen atmosphere at −20° C.was added isopropylmagnesium chloride (2M solution in THF, 6.5 mL, 13.0mmol) via dropwise addition. The mixture was then stirred for 1 hour at0° C. followed by the addition of a solution of8-formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butylester (273.5 mg, 1.54 mmol) in THF (2 mL) at −20° C. The mixture wasstirred at room temperature overnight, quenched with saturated aqueousNH₄Cl solution (5 mL), and extracted with EtOAc (2×200 mL). The combinedorganic extracts were washed with saturated aqueous NH₄Cl solution (40mL) and brine (40 mL), dried (Na₂SO₄), and concentrated under reducedpressure. The obtained residue was purified by flash columnchromatography on silica gel (10% EtOAc-hexanes to 90% EtOAc-hexanes) toobtain8-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid tert-butyl ester (590.2 mg) as yellow syrup. MS m/z: 678.0 (M+H)⁺.

To a solution of8-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid tert-butyl ester (562.7 mg, 0.91 mmol) in dioxane (4 mL) was addedpreactivated MnO₂ (932.9 mg, 9.12 mmol), and the resulted mixture washeated at 80° C. for two hour. The resulted mixture was cooled to r.t.,and filtered. The solid was washed with EtOAc (20 mL×3). EtOAc washingsolution was combined with dioxane filtrate, and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel to provide8-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid tert-butyl ester (510.2 mg) as yellow syrup. MS m/z: 676.0 (M+H)⁺.

A solution of8-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-2,3-dihydro-benzo[1,4]oxazine-4-carboxylicacid tert-butyl ester (510.2 mg) in 3 mL HCl (4M in dioxane) and water(1 mL) was heated at 80° C. for overnight. Upon cooling to roomtemperature, the mixture was concentrated and the residue was purifiedby flash column chromatography on silica gel to afford4-chloro-N-[5-chloro-2-(3,4-dihydro-2H-benzo[1,4]oxazine-8-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(210.2 mg) as white solid. MS m/z: 531.9 (M+H)⁺.

Example 291: (3-formyl-pyridin-2-yl)-carbamic Acid tert-butyl Ester

To 2-amino-pyridine-3-carbaldehyde (500 mg, 4.09 mmol) in CH₃CN (5 mL)was added (Boc)₂O (1.34 g, 6.14 mmol) and stirred at 50° C. for 24hours. Reaction mixture was diluted with EtOAc (50 mL), washed withbrine (3×25 mL), dried (Na₂SO₄), evaporated and purified by columnchromatography (SiO₂, 50% EtOAc in hexanes) to obtain(3-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (655 mg) in 72%yield. ESMS m/z (relative intensity): 123 [(M−100)+H]⁺ (100).

Example 292: [3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl)-pyridin-2-yl]-carbamicAcid tert-butyl Ester

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(3.27 g, 6.64 mmol) in THF (20 mL) under nitrogen atmosphere at 0° C.was added dropwise isopropylmagnesium chloride (2M solution in THF, 6.62mL, 13.25 mmol). The mixture was then stirred for 30 min at 0° C.followed by the addition of a solution of(3-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (590 mg, 2.65mmol) in THF (3 mL) at 0° C. The mixture was stirred at room temperaturefor 3 hours, quenched with saturated aqueous NH₄Cl solution (10 mL) andextracted with EtOAc (2×50 mL). Combined organic layers were washed withsaturated aqueous NH₄Cl solution (50 mL), brine (50 mL), dried(anhydrous Na₂SO₄) and concentrated under reduced pressure. Obtainedresidue was column purified (SiO₂, 50% EtOAc-hexanes) to obtain[3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl)-pyridin-2-yl]-carbamicacid tert-butyl ester (750 mg) in 44% yield as yellow solid. ESMS m/z(relative intensity): 637 (M+H)⁺ (100).

Example 293:3-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-pyridin-2-yl)-carbamicAcid tert-butyl Ester

A mixture of [3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl)-pyridin-2-yl]-carbamicacid tert-butyl ester (750 mg, 1.18 mmol) and MnO₂ (512.6 mg, 5.9 mmol)in THF (10 mL) was stirred at 50° C. for overnight. The reaction mixturewas cooled to room temperature, filtered through sintered funnel, washedwith THF (2×10 mL), dried (anhydrous Na₂SO₄) and concentrated. Theobtained residue was column purified (SiO₂, 50% EtOAc-hexanes) to afford(3-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-pyridin-2-yl)-carbamicacid tert-butyl ester (456 mg) 61% in yield. ESMS m/z (relativeintensity): 635 (M+H)⁺ (100).

Example 294:N-[2-(2-amino-pyridine-3-carbonyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide

A mixture of(3-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-pyridin-2-yl)-carbamicacid tert-butyl ester (25 mg, 0.0394 mmol) in 5% H₂SO₄ in TFA (4 mL) andwater (1 mL) was stirred at 50° C. for 6 h. The reaction mixture wascooled to room temperature, evaporated to dryness and treated withsaturated aqueous NaHCO₃ solution until pH 7-8. The mixture wasextracted with EtOAc (2×15 mL), dried (anhydrous Na₂SO₄) andconcentrated. The obtained residue was column purified to affordN-[2-(2-amino-pyridine-3-carbonyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide(9.3 mg) in 48% yield. ESMS m/z (relative intensity): 491 (M+H)⁺ (100).

Example 295:4-chloro-N-{2-[(2-chloro-5-nitro-phenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(472 mg, 1.0 mmol) in THF (3 mL) under nitrogen atmosphere at 0° C. wasadded dropwise isopropylmagnesium chloride (2M solution in THF, 1.2 mL,2.4 mmol). The mixture was then stirred for 30 min at 0° C. followed bythe addition of a solution of 2-chloro-5-nitro-benzaldehyde (352.6 mg,1.9 mmol) at 0° C. The mixture was stirred at room temperature for 3hours, quenched with saturated aqueous NH₄Cl solution (5 mL) andextracted with EtOAc (2×25 mL). Combined organic layers were washed withsaturated aqueous NH₄Cl solution (25 mL), brine (25 mL), dried(anhydrous Na₂SO₄) and concentrated under reduced pressure. Obtainedresidue was column purified (SiO₂, 50% EtOAc-hexanes) to obtain4-chloro-N-{2-[(2-chloro-5-nitro-phenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(441 mg) in 76% yield. ESMS m/z (relative intensity): 580 (M+H)⁺ (100),602 (M+Na) (20).

Example 296:4-chloro-N-[2-(2-chloro-5-nitro-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution of4-chloro-N-{2-[(2-chloro-5-nitro-phenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(441 mg, 0.76 mmol) in CH₂Cl₂ (5 mL) was added Dess-Martin periodinane(645 mg, 1.52 mmol) and stirred for 6 h at room temperature. 10% Na₂S₂O₃(5 mL) and saturated aqueous NaHCO₃ solution (5 mL) was added andstirred for 30 min. Aqueous layer was separated and extracted with EtOAc(2×25 mL). Combined organic layers were washed with saturated aqueousNaHCO₃ solution (20 mL), brine (20 mL), dried (anhydrous Na₂SO₄),concentrated and purified (SiO₂, 40% EtOAc-hexanes) to obtain4-chloro-N-[2-(2-chloro-5-nitro-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(230 mg) as yellow syrup in 52% yield. ESMS m/z (relative intensity):545.9 (M−31)⁺ (100), 578 (M+H)⁺ (50), 599.9 (M+Na)⁺ (65).

Example 297:4-chloro-N-[2-(2-chloro-5-nitro-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[2-(2-chloro-5-nitro-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(230 mg, 0.398 mmol) in 4M HCl in dioxane (4 mL) and water (1 mL) was50° C. for overnight. Reaction mixture was cooled to room temperature,evaporated to dryness and treated slowly with saturated aqueous NaHCO₃solution until pH 7-8. The mixture was extracted with EtOAc (2×25 mL),dried (anhydrous Na₂SO₄) and concentrated. The obtained residue waspurified by flash chromatography (SiO₂, 50% EtOAc-hexanes) to afford4-chloro-N-[2-(2-chloro-5-nitro-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(136 mg) in 64% yield. ESMS m/z (relative intensity): 533.9 (M+H)⁺ (90),555.9 (M+Na)⁺ (100).

Example 298:N-[2-(5-amino-2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide

To Fe powder (61.3 mg, 1.09 mmol), AcOH (2 mL) was added dropwise andheated to 80° C. To it, a solution of4-chloro-N-[2-(2-chloro-5-nitro-benzoyl)-5-methyl-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(136 mg, 0.255 mmol) in AcOH (2 mL) was added slowly. After 30 min,reaction mixture was allowed to cool to room temperature and dilutedwith EtOAc (25 mL), filtered through a pad of Celite. The filter cakewas washed with EtOAc (25 mL) and the filtrate was concentrated. Theresidual liquid was slowly treated with saturated aqueous NaHCO₃solution, followed by small portions of solid NaHCO₃ to neutralize theAcOH, extracted with EtOAc (2×25 mL) and the extracts were dried(anhydrous Na₂SO₄), concentrated under reduced pressure and purified(SiO₂, EtOAc) to getN-[2-(5-amino-2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide(118 mg) in 92.2% yield. ESMS m/z (relative intensity): 504 (M+H)⁺(100).

Example 299:4-chloro-N-{2-[2-chloro-5-(3-methyl-ureido)-benzoyl]-5-methyl-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

Methylisocyanate (17 μL, 0.235 mmol) was added toN-[2-(5-amino-2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (59 mg, 0.117 mmol) in THF (2 mL) and AcOH (0.5 mL) andstirred at room temperature for 4 h. The reaction mixture was directlypurified by preparative HPLC (20-80% acetonitrile in water) to afford4-chloro-N-{2-[2-chloro-5-(3-methyl-ureido)-benzoyl]-5-methyl-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide (25 mg) in 38% yield. ¹H NMR (400 MHz, CDCl₃+CD₃OD) δ 8.14(m, 2H), 7.95 (m, 2H), 7.63 (d, 1H), 7.58 (dd, 1H), 7.41 (dd, 1H), 7.19(d, 1H), 2.76 (s, 3H), 2.42 (s, 3H); ESMS m/z (relative intensity): 561(M+H)⁺ (100).

Example 300:4-Chloro-N-[5-chloro-2-(2-chloro-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(250 mg, 0.506 mmol) was placed in a dry 2-neck 10 mL round-bottomflask. The flask was evacuated and purged with nitrogen, followed by theaddition of THF (1.27 mL). The homogeneous mixture was lowered to −5° C.and i-PrMgCl (0.53 mL, 2.0M) was added dropwise. Upon completion of theaddition, the reaction was stirred 90 minutes, followed by the additionof 2-chloro-N-methoxy-N-methyl-isonicotinamide (203 mg, 1.01 mmol). Thereaction was stirred overnight, during which the ice-bath warmed to roomtemperature. The resultant solution was quenched with 10% HCl anddiluted with EtOAc. The organics were washed with 10% HCl and saturatedsodium bicarbonate, dried with sodium sulfate, and concentrated in vacuoto afford the protected diaryl ketone.

A 10 mL round-bottom flask was charged with the crude ketone, HCl indioxane (2.15 mL, 4.0M), and water (0.72 mL). The solution was warmed to80° C. and stirred overnight. The following day, the reaction wasneutralized with saturated sodium bicarbonate and diluted with EtOAc.The organics were washed with 10% HCl and saturated sodium bicarbonate,dried with sodium sulfate, concentrated in vacuo, and purified viaautomated silica gel chromatography to afford the desired deprotectedchloropyridine: ¹H NMR (400 MHz, CDCl₃) δ 8.54 (d, 1H), 8.36 (d, 1H),8.20 (d, 1H), 8.18 (d, 1H), 8.00 (dd, 1H), 7.66-7.80 (m, 2H), 7.56 (dd,1H); MS (ES) M+H expect 509.9, found 509.9.

Example 301:4-Chloro-N-[5-chloro-2-(pyridine-2-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Following the procedure for example 300,4-chloro-N-[5-chloro-2-(pyridine-2-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamidewas produced fromN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(200 mg, 0.405 mmol) and pyridine-2-carboxylic acid methoxy-methyl-amide(135 mg, 0.810 mmol): ¹H NMR (400 MHz, CDCl₃) δ 8.64 (dd, 1H), 8.36 (dd,1H), 8.18 (dd, 1H), 8.07 (s, 1H), 7.78-7.88 (m, 3H), 7.54 (d, 1H),7.45-7.51 (m, 1H); MS (ES) (M+H)⁺ expected 476.0, found 475.9.

Example 302:4-Chloro-N-[5-chloro-2-(6-chloro-pyridine-2-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Following the procedure for example 300,4-chloro-N-[5-chloro-2-(6-chloro-pyridine-2-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamidewas produced fromN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(250 mg, 0.506 mmol) and 6-chloro-pyridine-2-carboxylic acidmethoxy-methyl-amide (203 mg, 1.01 mmol).

Example 303:4-Chloro-N-[5-chloro-2-(2-methanesulfonylamino-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Following the procedure for 300,4-chloro-N-[5-chloro-2-(2-methanesulfonylamino-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamidewas produced fromN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(784 mg, 1.59 mmol) and2-methanesulfonylamino-N-methoxy-N-methyl-isonicotinamide (165 mg, 0.635mmol): MS (ES) [M+H]⁺ expected 569.0, found 568.9.

Example 304:4-Chloro-N-[5-chloro-2-(6-hydroxy-pyridine-2-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A 2 dram vial was charged with4-chloro-N-[5-chloro-2-(6-chloro-pyridine-2-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(65 mg, 0.127 mmol), formic acid (2.0 mL) and water (0.50 mL). Theheterogeneous solution was warmed to 110° C. and stirred overnight. Thefollowing day, the resultant mixture was neutralized with saturatedaqueous sodium bicarbonate, diluted with EtOAc, and the organic layerwashed with saturated sodium bicarbonate. The combined organics weredried with sodium sulfate, concentrated in vacuo, and purified viaautomated silica gel chromatography to afford the desiredhydroxypyridine: MS (ES) (M+H)⁺ expected 492.0, found 491.9.

Example 305:4-Chloro-N-[5-chloro-2-(2-hydroxy-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-

A 1 dram vial was charged with4-chloro-N-[5-chloro-2-(2-chloro-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(25 mg, 0.045 mmol), formic acid (0.39 mL) and water (0.13 mL). Theheterogeneous solution was warmed to 100° C. and stirred overnight. Thefollowing day, starting material remained; therefore, an additional 0.26mL of formic acid was added. The reaction was subsequently warmed to110° C. and stirred overnight. The resultant mixture was neutralizedwith saturated aqueous sodium bicarbonate, diluted with EtOAc, and theorganic layer washed with saturated sodium bicarbonate. The combinedorganics were dried with sodium sulfate, concentrated in vacuo, andpurified via automated silica gel chromatography to afford the desiredhydroxypyridine: ¹H NMR (400 MHz, C₂D₆SO) δ 11.95 (bs, 1H), 8.46 (s,1H), 8.14 (s, 1H), 7.92 (d, 1H), 7.80-7.88 (m, 2H), 7.75 (d, 1H), 6.37(s, 1H), 6.29 (d, 1H); MS (ES) [M+H]⁺ expected 492.0, found 491.9.

Example 306:N-[2-(2-Amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide

N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(250 mg, 0.506 mmol) was placed in a dry 2-neck 10 mL round-bottomflask. The flask was evacuated and purged with nitrogen, followed by theaddition of THF (1.0 mL). The homogeneous mixture was lowered to −5° C.and iPrMgCl (0.53 mL, 2.0M) was added dropwise. Upon completion of theaddition, the reaction was stirred 90 minutes, followed by the slowaddition of2-[bis-(4-methoxy-benzyl)-amino]-N-methoxy-N-methyl-isonicotinamide (427mg, 1.01 mmol) dissolved in 1 mL THF. The reaction was stirredovernight, during which the ice-bath warmed to room temperature. Theresultant solution was quenched with 10% HCl and diluted with EtOAc. Theorganics were washed with 10% HCl and saturated sodium bicarbonate,dried with sodium sulfate, and concentrated in vacuo to afford theprotected diaryl ketone.

A 25 mL round-bottom flask was charged with the crude ketone,concentrated sulfuric acid (0.075 mL), and TFA (2.5 mL). The flask wassealed and stirred overnight. The following day, significant partiallyhydrolyzed N-hydroxymethyl sulfonamide remained; therefore, anadditional 0.15 mL of sulfuric acid was added and the flask was heatedto 50° C. for 8 h. The reaction was subsequently diluted with THF andneutralized with 2M NaOH to pH 7-8. The resultant mixture was furtherdiluted with EtOAc and the organics were washed with 10% HCl andsaturated sodium bicarbonate, dried with sodium sulfate, concentrated invacuo, and purified via automated silica gel chromatography then reversephase HPLC to afford the desired aminopyridine: ¹H NMR (400 MHz, CD₃OD)δ 8.42 (d, 1H), 8.10-8.14 (m, 2H), 7.86-7.94 (m, 2H), 7.70 (d, 1H), 6.91(d, 1H), 6.80 (dd, 1H); MS (ES) (M+H)⁺ expected 491.0, found 490.9.

Example 307:N-[2-(2-Amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide

Following the procedure for example 306,N-[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamidewas generated fromN-(2-bromo-5-chloro-pyridin-3-yl)-4-methyl-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(225 mg, 0.477 mmol) and2-[bis-(4-methoxy-benzyl)-amino]-N-methoxy-N-methyl-isonicotinamide (427mg, 1.01 mmol): ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, 1H), 8.16 (s, 1H),8.15 (d, 1H), 8.04 (s, 1H), 7.88 (dd, 1H), 7.38 (d, 1H), 6.84 (dd, 1H),6.74 (s, 1H), 4.57 (s, 2H), 2.50 (s, 3H); MS (ES) (M+H)⁺ expected 491.0,found 490.9.

Example 308:N-[5-Chloro-2-(2-methanesulfonylamino-pyridine-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide(140 mg, 0.272 mmol) in pyridine (0.75 mL) was added methanesulfonylchloride (0.042 mL, 0.544 mmol). The reaction was warmed to 50° C. andstirred 2.5 h. The resultant mixture was quenched with 10% HCl, dilutedwith EtOAc, and the organic layer washed with 10% HCl and saturatedsodium bicarbonate. The combined organics were dried with sodiumsulfate, concentrated in vacuo, and purified via automated silica gelchromatography to produce the desired sulfonamide.

A 10 mL round-bottom flask was charged with the protected sulfonamide(57 mg, (0.096 mmol), aqueous HCl (0.11 mL, 8.0M), and dioxane (0.21mL). The solution was warmed to 80° C. and stirred overnight. Thefollowing day, the reaction was neutralized with saturated sodiumbicarbonate and diluted with EtOAc. The organics were washed with 10%HCl and saturated sodium bicarbonate, dried with sodium sulfate,concentrated in vacuo, and purified via automated silica gelchromatography to afford the desired methanesulfonamidino pyridine: ¹HNMR (400 MHz, CD₃OD) δ 8.24 (d, 1H), 7.96 (d, 1H), 7.92 (d, 1H), 7.85(d, 1H), 7.63 (d, 1H), 7.36 (d, 1H), 7.07-7.11 (m, 2H), 3.26 (s, 3H),2.46 (s, 3H); MS (ES) (M+H)⁺ expected 549.0, found 549.0.

Example 309:2-Amino-N-{4-[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-pyridin-2-yl}-acetamide

To a mixture ofN-[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide(800 mg, 1.69 mmol), Boc-glycine (742 mg, 4.24 mmol),diisopropylethylamine (1.9 mL, 10.14 mmol) in methylene chloride (4 mL)was added propylphosphonic anhydride (2.68 mL, 50% solution in EtOAc,4.24 mmol) was added slowly. The resultant heterogeneous solution wasallowed to stir overnight at 45° C. The following day, the reaction wasdiluted with EtOAc, the organics were washed with saturated sodiumbicarbonate, aqueous saturated NH₄Cl and dried with sodium sulfate,concentrated in vacuo, and purified via automated silica gelchromatography to provide({4-[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-pyridin-2-ylcarbamoyl}-methyl)-carbamicacid tert-butyl ester.

A solution of({4-[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-pyridin-2-ylcarbamoyl}-methyl)-carbamicacid tert-butyl ester (45 mg) in CH₂Cl₂ was added TFA (200

L). The resulting mixture was stirred at room temperature for 3 h,concentrated under reduced pressure and the residue was re-dissolved inMeCN and purified by HPLC to provide2-amino-N-{4-[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-pyridin-2-yl}-acetamide.¹H NMR (400 MHz, DMSO-d₆) δ 11.16 (s, 1H), 8.48-8.46 (m, 1H), 8.19 (s,1H), 8.08 (br m, 3H), 7.89 (s, 1H), 7.78-7.76 (m, 2H), 7.55 (d, J=7.6Hz, 1H), 7.28-7.26 (m, 1H), 3.85 (s, 2H), 2.43 (s, 3H); MS m/z 528.0(M+H)⁺.

Example 310:4-chloro-N-{2-[2-(dimethylamino-methyleneamino)-pyridine-4-carbonyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(367 mg, 0.775 mmol) in THF (2 mL) under nitrogen atmosphere at 0° C.was added dropwise isopropylmagnesium chloride (2M solution in THF, 0.94mL, 1.866 mmol). The mixture was then stirred for 30 min at 0° C.followed by the addition of a solution of2-(dimethylamino-methyleneamino)-N-methoxy-N-methyl-isonicotinamide (349mg, 1.47 mmol) in THF (1 mL) at 0° C. The mixture was stirred at roomtemperature for 6 hours, quenched with saturated aqueous NH₄Cl solution(5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers werewashed with saturated aqueous NH₄Cl solution (25 mL), brine (25 mL),dried (anhydrous Na₂SO₄) and concentrated under reduced pressure.Obtained residue was column purified (SiO₂, 50% EtOAc-hexanes) to obtain4-chloro-N-{2-[2-(dimethylamino-methyleneamino)-pyridine-4-carbonyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (230 mg) in 52% yield. ESMS m/z (relative intensity): 570.1(M+H)⁺ (100).

Example 311:N-[2-(2-amino-pyridine-4-carbonyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-{2-[2-(dimethylamino-methyleneamino)-pyridine-4-carbonyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (23 mg, mmol) in 5% H₂SO₄ in TFA (4 mL) and water (1 mL) wasstirred at 50° C. for 2 days. The reaction mixture was cooled to roomtemperature, diluted with water (5 mL) and treated with saturatedaqueous NaHCO₃ solution slowly till pH 7-8. The mixture was extractedwith EtOAc (2×25 mL), dried (anhydrous Na₂SO₄) and concentrated. Theobtained residue was column purified (SiO₂, 10% MeOH—CH₂Cl₂) to affordN-[2-(2-amino-pyridine-4-carbonyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide (12 mg) in 63% yield. ¹H NMR (400 MHz, CDCl₃)δ10.75 (s, 1H), 8.24 (s, 1H), 8.18 (m, 1H), 8.07 (dd, 1H), 7.95 (d, 1H),7.75 (d, 1H), 7.63 (d, 1H), 7.15 (s, 1H), 6.95 (d, 1H), 2.25 (s, 3H);ESMS m/z (relative intensity): 471.0 (M+H)⁺ (100).

Example 312:4-Chloro-N-(2-formyl-5-methyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution ofN-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(750 mg, 1.59 mmol) in THF (3 mL) under nitrogen atmosphere at 0° C. wasadded dropwise isopropylmagnesium chloride (2M solution in THF). Themixture was then stirred for 30 min at 0° C. followed by the addition ofN,N-dimethylformamide (1.19 mL, excess) at 0° C. The mixture was stirredat room temperature for 3 hours, quenched with saturated aqueous NH₄Clsolution (5 mL) and extracted with EtOAc (2×25 mL). Combined organiclayers were washed with saturated aqueous NH₄Cl solution (25 mL), brine(25 mL), dried (anhydrous Na₂SO₄) and concentrated under reducedpressure. Obtained residue was column purified (SiO₂, 30% EtOAc-hexanes)to obtain4-chloro-N-(2-formyl-5-methyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(300 mg) in 44.7% yield. ESMS m/z (relative intensity): 390.9 (M−32+H)⁺(40), 423 (M+H)⁺ (40), 444.9 (M+Na)⁺ (40).

Example 313:4-Chloro-N-{5-chloro-2-[hydroxy-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide

To a solution of 4-iodo-1H-pyrazolo[3,4-b]pyridine (174.2 mg, 0.71 mmol)in THF (3 mL) under nitrogen atmosphere at 0° C. was added dropwiseisopropylmagnesium chloride (2M solution in THF, 1.06 mL, 2.13 mmol).The resulting yellow suspension was then stirred for 30 min at 0° C.followed by the addition of a solution of4-chloro-N-(2-formyl-5-methyl-pyridin-3-yl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(300 mg, 0.71 mmol) in THF (2 mL) at 0° C. The mixture was stirred atroom temperature for 3 hours, quenched with saturated aqueous NH₄Clsolution (5 mL) and extracted with EtOAc (2×25 mL). Combined organiclayers were washed with saturated aqueous NH₄Cl solution (25 mL), brine(25 mL), dried (anhydrous Na₂SO₄) and concentrated under reducedpressure. Obtained residue was column purified (SiO₂, 50% EtOAc-hexanes)to obtain4-chloro-N-{5-chloro-2-[hydroxy-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide (192 mg) in 50% yield. ESMS m/z (relative intensity): 542(M+H)⁺ (100), 564 (M+Na)⁺ (10).

Example 314:4-Chloro-N-methoxymethyl-N-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

To a solution of4-chloro-N-{5-chloro-2-[hydroxy-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methyl]-pyridin-3-yl}-3-trifluoromethyl-benzenesulfonamide (192 mg, 0.355 mmol) in CH₂Cl₂ (5 mL) was added Dess-Martinperiodinane (302 mg, 0.71 mmol) and stirred for 24 h at roomtemperature. 10% Na₂S₂O₃ (5 mL) and saturated aqueous NaHCO₃ solution (5mL) was added and stirred for 30 min. Aqueous layer was separated andextracted with EtOAc (2×25 mL). Combined organic layers were washed withsaturated aqueous NaHCO₃ solution (20 mL), brine (20 mL), dried(anhydrous Na₂SO₄), concentrated and purified (SiO₂, 50% EtOAc-hexanes)to obtain4-chloro-N-methoxymethyl-N-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(128 mg) in 67% yield. ESMS m/z (relative intensity): 508 (M−32+H)⁺(40), 540 (M+H)⁺ (40), 562 (M+Na) (40).

Example 315:4-Chloro-N-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-methoxymethyl-N-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(50 mg, 0.092 mmol) in 4M HCl in dioxane (4 mL) and water (1 mL) wasstirred at 70° C. for overnight. Reaction mixture was cooled to roomtemperature, evaporated to dryness and treated with saturated aqueousNaHCO₃ solution till pH 7-8. The mixture was extracted with EtOAc (2×25mL), dried (anhydrous Na₂SO₄) and concentrated. The obtained residue waspurified by flash chromatography (SiO₂, 70% EtOAc-hexanes) to afford4-chloro-N-[5-methyl-2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(28.9 mg) as yellow solid (after lyophilization) in 63% yield. ¹H NMR(400 MHz, CDCl₃) δ10.75 (s, 1H), 8.65 (d, 1H), 8.24 (m, 1H), 8.14 (d,1H), 8.08 (s, 1H), 7.94-7.99 (m, 2H), 7.59 (d, 1H), 7.58 (d, 1H), 2.48(s, 3H); ESMS m/z (relative intensity): 496 (M+H)⁺ (100).

Example 316:(S)-4-Chloro-N-(5-chloro-2-(4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide

General synthesis of amides: A 10 mL scintillation vial was charged withthe5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (164 mg, 0.4 mmol), freshly prepared 3,3-dimethylpiperidin-4-ol(0.56 mmol) ((M+H+), 130.1), HATU (192 mg, 0.5 mmol), DIEA (260 mg, 2mmol) and anhydrous DMF (1.5 mL). The resultant solution was heated to70° C. and stirred for 2 h. After cooled to room temperature, themixture was purified via preparative HPLC and dried (lyophilizer) toafford(S)-4-chloro-N-(5-chloro-2-(4-hydroxy-3,3-dimethylpiperidine-1-carbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide (1:2 mixture of rotamers): ¹H NMR (400 MHz, CDCl₃)(major rotamer) δ 9.54 (s, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.00 (d,1H), 7.88 (dd, 1H), 7.62 (d, 1H), 4.05 (m, 1H), 3.70 (d, 1H), 3.50 (m,2H), 3.40 (m, 1H), 3.10 (d, 1H), 1.82 (m, 2H), 1.00 (s, 3H), 0.92 (s,3H); MS (ES) (M+H)⁺ expected 526.0, found 526.0.

Example 317:5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-N-methyl-N-(pyridin-3-yl)picolinamide

5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-N-methyl-N-(pyridin-3-yl)picolinamidewas prepared according to method described in example 316: ¹H NMR (400MHz, CDCl₃) δ 8.62 (dd, 1H), 8.52 (s, 1H), 8.22 (d, 1H), 8.02 (dd, 1H),7.96 (d, 1H), 7.80 (s, 1H), 7.68 (m, 3H), 3.50 (s, 3H); MS (ES) (M+H)⁺expect 505.0, found 505.0.

Example 318:N-[5-Chloro-2-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide

Step 1

A 25 mL round-bottom flask was charged with4-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (308 mg, 1.0mmol), THF (4 mL) and the mixture was cooled to −78° C. Asec-butyllithium solution (1.4M in cyclohexane, 1.6 mL, 2.2 equiv.) wasadded dropwise and after 30 minutes, a solution of (R)-camphorsulfonyloxaziridine (573 mg, 2.5 equiv.) in 4 mL of THF was added rapidly. Thereaction mixture was then stirred for another 25 minutes at −78° C. andquenched with saturated ammonium chloride solution. The mixture wasallowed to reach room temperature and then extracted with ethyl acetate.The combined organic layers were washed with brine and dried over MgSO₄.Solvent was removed and the crude material was purified by flashchromatography on silica gel (10% EtOAc/hexanes). The desired productwas obtained as a colorless liquid (160 mg, 49%). MS: (M+H)/z=325.

Step 2

The product obtained from step 1 above (60 mg, 0.18 mmol) was dissolvedin 2 mL of methanol. Trimethylsilyl diazomethane (2.0M in ether, 1 mL)was added and the reaction mixture was stirred overnight at roomtemperature. Solvent was removed and the crude material was purified byflash chromatography on silica gel (10% EtOAc/hexanes). The desiredproduct was obtained as a colorless liquid (58 mg, 93%). MS:(M+H)/z=339.

Step 3

The product obtained from step 2 above (106 mg, 0.31 mmol) was dissolvedin 5 mL of acetonitrile. Then NaI (470 mg, 10 equiv.) was added followedby acetyl chloride (67

L, 3 equiv.). The reaction mixture was allowed to stir at 80° C. for 2hours, and then excess acetonitrile was removed in vacuo. A mixture of10% K₂CO₃ (10 mL) and 10% sodium bisulfite (10 mL) was added to theresidue and the mixture was extracted with ethyl acetate and washed withbrine. The combined organic layer was dried over MgSO₄ and concentratedin vacuo to give the crude product. To a solution of this crude productin THF (3 mL) was added 1M NaOH (0.5 mL). The mixture was stirred for 1hour at room temperature and quenched with saturated ammonium chloridesolution. The mixture was extracted with ethyl acetate, and the extractswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (20%EtOAc/hexanes). The desired product was obtained as a white solid (60mg, 86%). MS: (M+H)/z=275.

Step 4

The product obtained from step 3 above (157 mg, 0.57 mmol) was dissolvedin 5 mL of anhydrous DMF. Then NaH (25 mg, 60% dispersion in mineraloil) was added. After 30 minutes, triisopropylsilyl chloride (133

L, 1.1 equiv.) was added and the reaction mixture was stirred overnightat room temperature. The reaction was quenched with saturated ammoniumchloride solution, and the mixture was extracted with ethyl acetate. Theextracts were washed with brine, dried over MgSO₄ and concentrated invacuo. The crude material was purified by flash chromatography on silicagel (10% EtOAc/hexanes). The desired product was obtained as an oil (222mg, 90%). MS: (M+H)/z=431.

Step 5

The product obtained from step 4 above (120 mg, 0.28 mmol) was dissolvedin 3 mL of anhydrous THF and cooled to 0° C. Then isopropylmagnesiumchloride (280

L, 2.0M in THF) was added. After 45 minutes, anhydrous DMF (215

L, 10 equiv.) was added and the reaction mixture was warmed up to roomtemperature and stirred overnight. The reaction was quenched withsaturated ammonium chloride solution, and the mixture was extracted withethyl acetate. The extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel (5% EtOAc/hexanes). The desired product wasobtained as a pale yellow solid (46 mg, 50%). MS: (M+H)/z=333.

Step 6

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide(97 mg, 0.21 mmol) in THF (3 mL) at 0° C. was added isopropylmagnesiumchloride (187

L, 2.0M in THF) dropwise. After 45 minutes, a solution of the productobtained from step 5 above (62 mg, 0.19 mmol) in THF was added. Thereaction mixture was warmed up to room temperature and stirredovernight. The reaction was quenched with saturated ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The extractswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (20%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (95 mg, 70%). MS: (M+H)/z=727.

Step 7

The product obtained from step 6 above (77 mg, 0.11 mmol) was dissolvedin 3 mL of dichloromethane. To the resultant solution was addedDess-Martin periodinane (72 mg, 1.6 equiv.) and stirred overnight atroom temperature. The reaction was quenched with 10% Na₂S₂O₃, and themixture was extracted with ethyl acetate. The extracts were washed withsaturated NaHCO₃, brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (20%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (59 mg, 77%). MS: (M+H)/z=725.

Step 8

The product obtained from step 7 above (59 mg, 0.081 mmol) was dissolvedin 4 mL of HCl-dioxane (4.0M) and 1 mL of water. The mixture was heatedat 85° C. for 30 minutes and quenched with saturated NaHCO₃. The mixturewas extracted with ethyl acetate. The extracts were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel (80% EtOAc/hexanes). Thedesired product was obtained as a yellow solid (34 mg, 80%). ¹HNMR: (400MHz, CDCl₃) δ 8.17 (dd, J=7.2, 2.4 Hz, 2H), 8.13 (d, J=1.6 Hz, 1H), 8.12(s, 1H), 7.97 (dd, J=8.0, 2.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.34 (t,J=2.8 Hz, 1H), 6.10 (dd, J=3.6, 2.0 Hz, 1H), 3.68 (s, 3H), 2.54 (s, 3H);MS: (M+H)/z=525.

Example 319:N-[5-Chloro-2-(7-hydroxy-5-methoxy-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethylBenzenesulfonamide

To a stirred solution ofN-[5-chloro-2-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide(13 mg, 0.025 mmol) in chloroform (5 mL) was added peracetic acid (20

L, 32% wt in acetic acid). The reaction mixture was stirred for 2 daysat room temperature and quenched with saturated NaHCO₃. The mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (80% EtOAc/hexanes). The desiredproduct was obtained as a yellow solid (11 mg, 80%). ¹H NMR: (400 MHz,CDCl₃) δ 8.16 (s, 2H), 8.11 (s, 1H), 8.00 (s, 1H), 7.96 (dd, J=8.4, 2.0Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.34 (d, J=3.6 Hz, 1H), 6.25 (d, J=3.2Hz, 1H), 3.61 (s, 3H), 2.53 (s, 3H); MS: (M+H)/z=541.

Example 320:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid ethyl-(1H-pyrazol-3-yl)-amide

Step 1

A mixture of acetaldehyde (0.074 mL, 1.32 mmol), acetic acid (0.078 mL,1.32 mmol) and 3-amino-pyrazole-1-carboxylic acid tert-butyl ester (200mg, 1.1 mmol) in DCM (5 mL) was stirred at RT for 1 hour. To the mixturewas added sodium triacetoxyborohydride (467 mg, 2.2 mmol), stirredovernight. The mixture was extracted with ethyl acetate, washed withwater, dried and concentrated. The residue was purified by flash columnto afford 3-amino-pyrazole-1-carboxylic acid tert-butyl ester.

Step 2

A mixture of5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (100 mg, 0.24 mmol), 3-amino-pyrazole-1-carboxylic acid tert-butylester (51 mg, 0.24 mmol), HATU (160 mg, 0.42 mmol), and TEA (0.13 mL) inDMF (1.5 mL) was stirred at room temperature overnight. It was purifiedwith HPLC to give3-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-pyrazole-1-carboxylicacid tert-butyl ester.

Step 3

3-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-pyrazole-1-carboxylicacid tert-butyl ester from step 2 was dissolved in a mixture of DCM andTFA (1:1) (5 mL). It was stirred at RT for 1 hour, concentrated,purified with HPLC to give5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid ethyl-(1H-pyrazol-3-yl)-amide: 1H NMR (400 MHz, CDCl₃) δ 8.11 (d,1H), 8.0 (d, 1H), 7.94 (m, 1H), 7.88 (br, 1H), 7.6 (d, 1H), 7.37 (br,1H), 5.8 (s, 1H), 3.8 (m, 2H), 1.1 (m, 3H); MS m/z: 508 (M+H)⁺.

Example 321:5-Chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid ethyl-(1H-pyrazol-3-yl)-amide

The title compound was prepared by procedure analogous to that describedin Example 320 using5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid: ¹H NMR (400 MHz, CDCl₃) δ 8.1 (d, 2H), 7.9 (d, 2H), 7.3 (m, 2H),5.5 (s, 1H), 3.8 (m, 2H), 2.5 (s, 3H), 1.1 (m, 3H); MS m/z: 488 (M+H)⁺.

Example 322:Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid isopropyl-(1H-pyrazol-3-yl)-amide

Step 1

A mixture of acetone (0.1 mL, 1.4 mmol), acetic acid (0.078 mL, 1.43mmol) and 3-amino-pyrazole-1-carboxylic acid tert-butyl ester (200 mg,1.1 mmol) in DCM (5 mL) was stirred at RT for 1 hour. Sodiumtriacetoxyborohydride (467 mg, 2.2 mmol) was added and the mixturestirred overnight. The mixture was extracted with ethyl acetate, washedwith water, dried and concentrated. The residue was purified by flashcolumn to give 3-Isopropylamino-pyrazole-1-carboxylic acid tert-butylester.

Step 2

A mixture of5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (100 mg, 0.24 mmol), oxalyl chloride (2N in DCM, 0.24 mL, 0.48mmol), TEA (0.064 mL) in THF (1 mL) was stirred at RT for 2 hours andthen evaporated to dryness to give5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonylchloride.

A mixture of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonylchloride (100 mg, 0.2 mmol), 3-isopropylamino-pyrazole-1-carboxylic acidtert-butyl ester (54 mg, 0.24 mmol), TEA (0.88 mL) in THF was stirred atRT for 2 hours and then purified by flash column to give3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-isopropyl-amino)-pyrazole-1-carboxylicacid tert-butyl ester.

Step 3

3-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-isopropyl-amino)-pyrazole-1-carboxylicacid tert-butyl ester from step 2 was dissolved in a mixture of 4M HClin dioxane (4 mL) and water (1 mL), heated to 85° C. for 2 h. Thesolvent was evaporated and the residue was purified with HPLC to give5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid isopropyl-(1H-pyrazol-3-yl)-amide. MS m/z: 522 (M+H)⁺.

Example 323:5-Chloro-3-(4-chloro-3-methyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid ethyl-(1H-pyrazol-3-yl)-amide

5-Chloro-3-(4-chloro-3-methyl-benzenesulfonylamino)-pyridine-2-carboxylicacid ethyl-(1H-pyrazol-3-yl)-amide was prepared by procedure analogousto that described in Example 320 using5-chloro-3-(4-chloro-3-methyl-benzenesulfonylamino)-pyridine-2-carboxylicacid. MS m/z: 454 (M+H)⁺.

Example 324:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid ethyl-(1H-indazol-3-yl)-amide

Step 1

A mixture of5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonylchloride (100 mg, 0.24 mmol), 3-ethylamino-indazole-1-carboxylic acidtert-butyl ester (62.6 mg, 0.24 mmol), and TEA (0.64 mL) in THF (1 mL)was stirred at 60° C. for 2 hours and then purified by flash column togive3-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-indazole-1-carboxylicacid tert-butyl ester.

Step 2

3-{[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-indazole-1-carboxylicacid tert-butyl ester was dissolved in a mixture of DCM and TFA (1:1) (5mL). It was stirred at RT for 1 hour, concentrated, purified with HPLCto give5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid ethyl-(1H-indazol-3-yl)-amide. MS m/z: 557.9 (M+H)⁺.

Example 325:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid (6-amino-pyridin-2-yl)-ethyl-amide

Step 1

To a solution of pyridine-2,6-diamine (2 g, 18.3 mmol) was added LiHMDS(20 mL, 20 mmol). The resultant solution was stirred at ambienttemperature for 30 minutes, followed by the addition of (Boc)₂O (4.8 g,22 mmol) and stirred for 3 hours. The mixture was stirred 3 h, dilutedwith ethyl acetate, washed with water, and purified by flash column togive (6-amino-pyridin-2-yl)-carbamic acid tert-butyl ester.

Step 2

The title compound was prepared by reductive amination procedureanalogous to that described in step 1 of example 320 using(6-amino-pyridin-2-yl)-carbamic acid tert-butyl ester.

Step 3

The title compound was prepared by procedure analogous to that describedin example 325, step 2 using5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonylchloride and (6-ethylamino-pyridin-2-yl)-carbamic acid tert-butyl ester.

Step 4

The title compound was prepared by procedure analogous to that describedin example 322, step 3 using(6-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-pyridin-2-yl)-carbamicacid tert-butyl ester. MS m/z: 534 (M+H).

Example 326:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid (3-amino-phenyl)-isopropyl-amide

Step 1

The functionalized amine was prepared according to the proceduredescribed in step 1 of Example 322 using (6-amino-pyridin-2-yl)-carbamicacid tert-butyl ester in reductive amination to give(6-Isopropylamino-pyridin-2-yl)-carbamic acid tert-butyl ester.

Step 2

The secondary amide was prepared according to the procedure described instep 1 of Example 323 using (6-isopropylamino-pyridin-2-yl)-carbamicacid tert-butyl ester to give(6-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-isopropyl-amino}-pyridin-2-yl)-carbamicacid tert-butyl ester.

Step 3

The title compound was prepared according to the procedure described instep 2 of Example 323 to give5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (6-amino-pyridin-2-yl)-isopropyl-amide. MS m/z: 548 (M+H)⁺.

Example 327:5-Chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid (6-amino-pyridin-2-yl)-ethyl-amide

Step 1

The acid chloride was prepared according to the procedure described inExample 323, step 2 using5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid to give the desired product.

The corresponding amide was prepared according to the proceduredescribed in step 1 of example 325 using5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonylchloride to give(6-{[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-pyridin-2-yl)-carbamicacid tert-butyl ester.

Step 2

The title compound was prepared by procedure analogous to that describedin example 325, step 2 using(6-{[5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-pyridin-2-yl)-carbamicacid tert-butyl ester to give5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (6-amino-pyridin-2-yl)-ethyl-amide. MS m/z: 514 (M+H)⁺.

Example 328:4-Chloro-N-[5-chloro-2-(2-chloro-5-pyrazol-1-yl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Step 1

2-Chloro-5-iodo-N-methoxy-N-methyl-benzamide was synthesized from2-chloro-5-iodobenzoic acid according to example 214.

Step 2

A mixture of 2-chloro-5-iodo-N-methoxy-N-methyl-benzamide (700 mg, 2.15mmol), pyrazole (439 mg, 6.45 mmol), 8-hydroxyquinoline (62.7 mg, 0.43mmol), copper iodide (81.7 mg, 0.43 mmol), and potassium carbonate (445mg, 3.22 mmol) in DMSO (2 mL) was stirred at 115° C. overnight. Theresultant solution was diluted with ethyl acetate, washed with water,dried over sodium sulfate, and purified by HPLC to give the desiredproduct. (M+H)⁺: 266.

Step 3

To a solution of 2-chloro-N-methoxy-N-methyl-5-pyrazol-1-yl-benzamide(280 mg, 1.05 mmol) was added DIBAL-H (1.16 mL, 1.16 mmol) slowly at−78° C. The reaction was stirred 2 h, quenched with water, extractedwith ether, concentrated, and purified by flash chromatography to give2-chloro-5-pyrazol-1-yl-benzaldehyde.

Step 4

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(356 mg, 0.68 mmol) in THF was added isopropylmagnesium chloride (0.75mL, 1.5 mmol) slowly at 0° C. One hour later2-chloro-5-pyrazol-1-yl-benzaldehyde (140 mg, 0.68 mmol) was added andwarmed up the reaction mixture to RT for 2 hours, quenched with water,extracted with ethyl acetate, concentrated and purified by flash columnto give4-chloro-N-{5-chloro-2-[(2-chloro-5-pyrazol-1-yl-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.

Step 5

A mixture of4-chloro-N-{5-chloro-2-[(2-chloro-5-pyrazol-1-yl-phenyl)-hydroxy-methyl]-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(400 mg, 0.64 mol), Dess-Martin periodinane (409 mg, 0.96 mmol), in DCMwas stirred at RT for 2 hours and then purified by flash column to give4-chloro-N-[5-chloro-2-(2-chloro-5-pyrazol-1-yl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.

Step 6

4-Chloro-N-[5-chloro-2-(2-chloro-5-pyrazol-1-yl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidefrom step 5 was dissolved in a mixture of 4M HCl in dioxane (8 mL) andwater (2 mL) and heated at 85° C. for 2 h. The solvent was evaporatedand the residue was purified via HPLC to give4-chloro-N-[5-chloro-2-(2-chloro-5-pyrazol-1-yl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide:¹H NMR (400 MHz, CDCl₃) δ 8.2 (m, 3H), 8.0 (m, 1H), 7.9 (s, 1H), 7.7 (m,4H), 7.45 (d, 1H), 6.45 (s, 1H); MS m/z: 576.9 (M+H)⁺.

Example 329:4-Chloro-N-[5-chloro-2-(2-morpholin-4-yl-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Step 1

A mixture of 2-chloro-N-methoxy-N-methyl-isonicotinamide (800 mg, 4mmol), morpholine (452 mg, 5.2 mmol), sodium tert-butoxide (500 mg, 5.2mmol),1,3-bis(2,6-di-isopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinonepalladium(0) dimer in dioxane (4 mL) was stirred at 80° C. overnight.The mixture was diluted with ethyl acetate, washed with water andpurified by flash column to giveN-methoxy-N-methyl-2-morpholin-4-yl-isonicotinamide.

Step 2

To a solution ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(590 mg, 1.2 mmol) in THF (2 mL) was added isopropylmagnesium chloride(1.3 mL, 2.6 mmol) slowly at 0° C. One hour later,N-methoxy-N-methyl-2-morpholin-4-yl-isonicotinamide (300 mg, 1.2 mmol)was added and warmed up to RT while stirring overnight, quenched withwater, extracted with ethyl acetate, concentrated and purified by flashcolumn to give4-chloro-N-[5-chloro-2-(2-morpholin-4-yl-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.

Step 3

4-Chloro-N-[5-chloro-2-(2-morpholin-4-yl-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidefrom step 2 was dissolved in a mixture of 4M HCl in dioxane (8 mL) andwater (2 mL), heated to 85° C. for 2 h. The solvent was evaporated andthe residue was purified with HPLC to give4-chloro-N-[5-chloro-2-(2-morpholin-4-yl-pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide.MS m/z: 561 (M+H)⁺.

Example 330:N-{5-Chloro-2-[2-(2-hydroxy-ethylamino)-pyridine-4-carbonyl]-pyridin-3-yl}-4-methyl-3-trifluoromethyl-benzenesulfonamide

Step 1

A mixture of (tert-butyl-dimethyl-silanyloxy)-acetaldehyde (177.7 mg,1.02 mmol), acetic acid (0.051 mL, 0.85 mmol) andN-[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide(400 mg, 0.85 mmol) in DCM (3 mL) was stirred at RT for 1 hour. To themixture was added sodium triacetoxyborohydride (360.8 mg, 1.7 mmol),stirred overnight. The mixture was extracted with ethyl acetate, washedwith water, dried and concentrated. The residue was purified by flashcolumn to affordN-[2-({2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-pyridin-4-yl}-hydroxy-methyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide.

Step 2

To the dioxane (1 mL) solution ofN-[2-({2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-pyridin-4-yl}-hydroxy-methyl)-5-chloro-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamidefrom step 1, was added MnO₂ (440 mg, 5 mmol). The mixture was stirred at80° C. for 1 hour, filtered, concentrated. The deprotection wasperformed in 4M HCl in dioxane (4 mL) and water (1 mL) for 1 hour at RT.The solvent was evaporated and the residue was purified with HPLC togiveN-{5-chloro-2-[2-(2-hydroxy-ethylamino)-pyridine-4-carbonyl]-pyridin-3-yl}-4-methyl-3-trifluoromethyl-benzenesulfonamide:¹H NMR (400 MHz, CDCl₃) δ 8.3 (s, 1H), 8.15 (d, 2H), 8.05 (s, 1H), 7.9(d, 1H), 7.4 (d, 1H), 6.7 (m, 2H), 3.8 (m, 2H), 3.5 (m, 2H), 2.5 (s,3H); MS m/z: 515 (M+H)⁺.

Example 331:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid (2H-pyrazol-3-yl)-amide

A 0° C. mixture of5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (41 mg, 0.1 mmol, 1 equiv) and 3-aminopyrazole (21 mg, 2.5 equiv)in 0.5 mL of pyridine was treated with 11

L (1.1 equiv) of POCl₃ for 5 minutes. After addition of 1 mL of water,the mixture was subjected to preparative reverse phase HPLC to give5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (2H-pyrazol-3-yl)-amide. ¹H NMR (400 MHz, CDCl₃) δ 11.95 (s, 1H),10.37 (s, 1H), 8.24 (m, 2H), 8.18 (s, 1H), 8.00 (dd, 1H), 7.63 (d, 1H),7.60 (d, 1H), 6.80 (d, 1H); MS (ES) (M+H)⁺ expected 480.0, found 480.0.

Example 332: 5-Chloro-thiophene-2-sulfonic acid[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-amide

Following the procedure for example 24, 5-chloro-thiophene-2-sulfonicacid (2-bromo-5-chloro-pyridin-3-yl)-amide was synthesized from5-chloro-thiophene-2-sulfonyl chloride and2-bromo-5-chloro-pyridin-3-ylamine.

5-Chloro-thiophene-2-sulfonic acid(2-bromo-5-chloro-pyridin-3-yl)-methoxymethyl-amide was synthesizedaccording to procedure described in example 25.

5-Chloro-thiophene-2-sulfonic acid[2-(2-amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-amide wasprepared according to procedure described in example 29. ¹H NMR (400MHz, DMSO-d₆) δ 8.45 (s, 1H), 8.00 (d, 1H), 7.8 (d, 1H), 7.39 (d, 1H),7.18 (dd, 1H), 7.05 (s, 1H), 6.96 (dd, 1H); MS (ES) (M+H) expected429.0, found 429.0.

Example 333:N-[2-(2-Amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-chloro-3-isopropoxy-benzenesulfonamide

N-[2-(2-Amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-chloro-3-isopropoxy-benzenesulfonamidewas prepared following the procedures described in example 332. Massspectrum m/z 481.0 (M+1), expected 481.0.

Example 334:N-[2-(2-Amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-chloro-3-ethoxy-benzenesulfonamide

N-[2-(2-Amino-pyridine-4-carbonyl)-5-chloro-pyridin-3-yl]-4-chloro-3-ethoxy-benzenesulfonamidewas prepared following the procedures described in example 332. Massspectrum m/z 481.0 (M+1), expected 481.0.

Example 335:N-[2-(2-Amino-pyridine-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamide

N-[2-(2-Amino-pyridine-4-carbonyl)-pyridin-3-yl]-4-methyl-3-trifluoromethyl-benzenesulfonamidewas prepared following the procedures described in example 332. Massspectrum m/z 437.0 (M+1), expected 437.0.

Example 336:4-Chloro-N-[5-chloro-2-((R)-3-methyl-morpholine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Step 1

To a mixture of (R)-2-amino-propan-1-ol (2.0 g, 26.6 mmol) in 150 mL ofDCM at −40° C. under nitrogen atmosphere was added dropwise chloroacetylchloride (2.3 mL, 29.2 mmol) in 60 mL of DCM. The mixture was graduallywarmed to 0° C. and was stirred for 2 hours. After the removal of thesolvents the residue was diluted with 50 mL of 1:1 ethyl acetate/hexane,stirred for 30 min and filtered. The filtrate was concentrated to afford2-chloro-N—((R)-2-hydroxy-1-methyl-ethyl)-acetamide as a liquid.

Step 2

To a mixture of 2-chloro-N—((R)-2-hydroxy-1-methyl-ethyl)-acetamideobtained above in 175 mL of isopropanol and 120 mL of DCM was addedt-BuOK (6 g) in 120 mL of isopropanol over 40 min. The mixture wasstirred for another 40 min and was neutralized with concentrated HCluntil pH was 6.5. The mixture was concentrated and the residue wasdiluted with 150 mL of water and 150 mL of ethyl acetate. The aqueouslayer was extracted with ethyl acetate, the organic layers were combinedand dried. Removal of the solvents afforded the desired(R)-5-methyl-morpholin-3-one which was used directly at next step.

Step 3

To a mixture of (R)-5-methyl-morpholin-3-one (237 mg. 2.0 mmol) in 2 mLof THF was added 4.0 mL of LAH/THF (1.0M), the resulting mixture wasstirred overnight at room temperature. To the mixture was slowly addedice-cooled water and then was dried over Na₂SO₄. Removal of the solventsafforded (R)-3-methyl-morpholine as a liquid.

Step 4

A mixture of5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (63 mg, 0.152 mmol), (R)-3-methyl-morpholine (100 mg, 1.0 mmol),DIEA (0.132 mL, 0.76 mmol) and HATU (86 mg, 0.23 mmol) in 1.5 mL of DMFwas stirred at room temperature for 4 hours. The mixture was directlyapplied for preparative HPLC (20-80% acetonitrile in water) to affordthe title compound as a white solid: ¹H NMR: (CDCl₃, ppm) δ 8.24 (d,1H), 8.11 (m, 1H), 8.02 (m, 1H), 7.93 (m, 1H), 7.63 (d, 1H), 4.60 (m,1H), 4.29 (m, 1H), 3.77 (m, 2H), 3.59 (m, 1H), 3.38 (m, 2H), 1.28 (m,3H); MS: (M+H)/z=498.0.

Example 337:2-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]benzoicAcid Methyl Ester

A mixture of2-[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]benzoicacid (20 mg), 4N HCl/dioxane (1 mL) and 1.5 mL of methanol was refluxedovernight. After cooled to room temperature, the mixture wasconcentrated and the residue was diluted with ethyl acetate, washed withsodium bicarbonate and brine and dried. Removal of the solvents affordedthe title compound as an off white solid: ¹H NMR: (CDCl₃, ppm) δ 11.20(s, 1H), 8.22 (m, 2H), 8.04 (m, 2H), 7.94 (m, 1H), 7.62 (m, 2H), 7.54(m, 1H), 7.31 (m, 1H), 3.54 (s, 3H); MS: (M+H)/z=533.0.

Example 338:4-Chloro-N-[5-chloro-2-(4-oxo-piperidine-1-carbonyl)-pyridin-3-yl]-3-trifluoromethylbenzenesulfonamide

A mixture of5-chloro-3-(4-chloro-3-methyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (415 mg, 1.0 mmol), piperidin-4-one hydrochloride (500 mg, 3.0mmol), DIEA (0.695 mL, 4.0 mmol), and 1-propane phosphonic acid cyclicanhydride (T₃P, 0.783 mL, 4.5 mmol) in 5.0 mL of DCM was stirred at roomtemperature for 4 hours. The mixture was directly applied for flashcolumn (40% ethyl acetate in hexane) to afford the title compound as awhite solid: ¹H NMR: (CDCl₃, ppm) δ 9.80 (s, 1H), 8.27 (d, 1H), 8.13 (d,1H), 8.02 (d, 1H), 7.92 (dd, 1H), 7.63 (d, 1H), 3.91 (t, 2H), 3.75 (t,2H), 2.57 (t, 4H); MS: (M+H)/z=496.0.

Example 339:4-Chloro-N-[5-chloro-2-(4-hydroxy-piperidine-1-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[5-chloro-2-(4-oxo-piperidine-1-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide(20 mg), sodium borohydride (10 mg) in 1 mL of methanol was stirred atroom temperature overnight. To the mixture was added water and theresulting mixture was extracted with ethyl acetate three times. Theorganic layer was washed with brine and dried. After the removal ofsolvents the residue was further purified by flash column (50% ethylacetate in hexane) to afford the title compound as a white solid: ¹HNMR: (CDCl₃, ppm) δ 8.12 (d, 1H), 8.09 (d, 1H), 7.95 (dd, 1H), 7.80 (d,1H), 7.62 (d, 1H), 4.05 (m, 1H), 3.88 (m, 1H), 3.47 (m, 1H), 3.36 (m,1H), 3.02 (m, 1H), 1.94 (m, 1H), 1.73 (m, 1H), 1.58 (m, 1H), 1.48 (m,2H); MS: (M+H)/z=498.0.

Example 340:(S)-1-[5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-pyrrolidine-2-carboxylicAcid Methyl Ester

A mixture of5-chloro-3-(4-chloro-3-methyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (300 mg, 0.725 mmol), (S)-pyrrolidine-2-carboxylic acid methylester (165 mg, 1.0 mmol), DIEA (0.695 mL, 4.0 mmol), and1-propylphosphonic acid cyclic anhydride (T₃P, 0.636 mL, 1.0 mmol) in2.0 mL of DCM was stirred at room temperature for 4 hours. The mixturewas directly applied for flash column (20% ethyl acetate in hexane) toafford the title compound as a white solid: ¹H NMR: (CD₃OD, ppm) δ 8.15(m, 1H), 8.02 (m, 2H), 7.86 (m, 1H), 7.70 (m, 1H), 4.63 (m, 1H), 3.75(s, 3H), 3.69 (m, 1H), 3.43 (m, 1H), 2.29 (m, 1H), 1.94 (m, 3H); MS(M+H)/z=526.0.

Example 341:4-tert-Butyl-N-[5-chloro-2-(imidazo[1,2-a]pyridine-6-carbonyl)-pyridin-3-yl]-benzenesulfonamideand4-tert-Butyl-N-[5-chloro-2-(3-chloro-imidazo[1,2-a]pyridine-6-carbonyl)-pyridin-3-yl]-benzenesulfonamide

Following the procedure for 26,4-tert-butyl-N-[5-chloro-2-(hydroxy-imidazo[1,2-a]pyridin-6-yl-methyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamidewas produced fromN-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(250 mg, 0.558 mmol) and imidazo[1,2-a]pyridine-6-carbaldehyde (179 mg,1.23 mmol).

The crude alcohol was dissolved in methylene chloride (2.5 mL), followedby the addition of the Dess-Martin periodinane (592 mg, 1.40 mmol). Theresultant solution was stirred 4 h and then quenched with aqueous sodiumthiosulfate. The mixture was diluted with EtOAc and the organics werewashed with aqueous sodium thiosulfate and saturated sodium bicarbonate,dried with sodium sulfate, concentrated in vacuo, and purified viaautomated silica gel chromatography to afford the biaryl ketone.

A 10 mL round-bottom flask was charged with the above protectedsulfonamide (40 mg), 0.078 mmol), HCl in dioxane (1.6 mL, 4.0M), andwater (0.50 mL). The solution was warmed to 70° C. and stirredovernight. The following day, the reaction was neutralized withsaturated sodium bicarbonate and diluted with EtOAc. The organics werewashed with 10% HCl and saturated sodium bicarbonate, dried with sodiumsulfate, concentrated in vacuo, and purified via automated silica gelchromatography to generate the desired imidazo[1,2-a]pyridine: ¹H NMR(400 MHz, CDCl₃) (10.82 (bs, 1H), 9.22 (s, 1H), 8.33 (d, 1H), 8.21 (d,1H), 7.77 (d, 2H), 7.69-7.76 (m, 2H), 7.59-7.64 (m, 2H), 7.43 (d, 2H),1.21 (s, 9H); MS (ES) (M+H)⁺ expected 469.1, found 469.1.

Example 342:N-{2-[(6-Amino-pyridin-3-yl)-methoxyimino-methyl]-5-chloro-pyridin-3-yl}-4-tert-butyl-benzenesulfonamideandN-{2-[(6-Amino-pyridin-3-yl)-methoxyimino-methyl]-5-chloro-pyridin-3-yl}-4-tert-butyl-benzenesulfonamide

A 1-dram vial was charged withN-[2-(6-amino-pyridine-3-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide(12.5 mg, 0.056 mmol), methoxylamine hydrochloride (14 mg, 0.327 mmol),pyridine (0.05 mL), and ethanol (0.05 mL). The reaction vessel waswarmed to 60° C. and stirred overnight. The following day, the mixturewas acidified with 0.1% aqueous TFA/0.1% TFA in acetonitrile andpurified via preparatory HPLC to afford a mixture of the cis and transmethoxime: (More polar isomer)¹H NMR (400 MHz, CD₃OD) (8.46 (d, 1H),8.18 (dd, 1H), 7.50-7.68 (m, 6H), 6.98 (dd, 1H), 3.90 (s, 3H), 1.33 (s,9H); MS (ES) (M+H)⁺ expected 474.1, found 474.1; (Less polar isomer)¹HNMR (400 MHz, CD₃OD) δ 8.24 (d, 1H), 8.03 (d, 1H), 7.88 (dd, 1H), 7.74(d, 2H), 7.55-7.60 (m, 3H), 6.93 (dd, 1H), 4.11 (s, 3H), 1.30 (s, 9H);MS (ES) (M+H)⁺ expected 474.1, found 474.1.

Example 343:N-[4-Chloro-2-(pyridine-4-carbonyl)-phenyl]-methanesulfonamide

A 250 mL flask was charged with(2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone (10.0 g, 43.1 mmol) andpyridine (43 mL) under nitrogen. To the resultant solution was addedmethanesulfonyl chloride (7.06 mL, 90.5 mmol) and the reaction wasstirred at room temperature overnight. The following morning, theorganics were concentrated in vacuo at 60° C., followed by hydrolysis ofthe bis-sulfonamide employing THF (65 mL) and sodium hydroxide (65 mL,4.0M). The resultant homogeneous solution was stirred at roomtemperature for 120 min. Upon completion of the hydrolysis, the THF wasremoved under reduced pressure and the pH of the aqueous layer wasadjusted to 5-6 with 6M HCl. The resultant solution was diluted withEtOAc and the organics were washed with 10% HCl and saturated sodiumbicarbonate, dried with sodium sulfate, concentrated in vacuo, andpurified via automated silica gel chromatography to generate the desiredmethanesulfonamide: MS (ES) (M+H)⁺ expected 311.0, found 311.1.

Example 344:N-{2-[(6-Amino-pyridin-3-yl)-ethoxyimino-methyl]-5-chloro-pyridin-3-yl}-4-tert-butyl-benzenesulfonamide

Following the procedure for 342,N-[2-(6-amino-pyridine-3-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide(15 mg, 0.034 mmol) was converted to its corresponding ethoxime: (Lesspolar isomer)¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, 1H), 8.03 (d, 1H), 7.89(dd, 1H), 7.74 (d, 2H), 7.58-7.60 (m, 3H), 6.93 (dd, 1H), 4.37 (q, 2H),1.41 (t, 3H), 1.30 (s, 9H); MS (ES) (M+H)⁺ expected 488.1, found 488.1.

Example 345:N-{2-[(6-Amino-pyridin-3-yl)-isopropoxyimino-methyl]-5-chloro-pyridin-3-yl}-4-tert-butyl-benzenesulfonamide

Following the procedure for 342,N-[2-(6-amino-pyridine-3-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide(15 mg, 0.034 mmol) was converted to its corresponding isopropyl oxime:(Less polar isomer)¹H NMR (400 MHz, CD₃OD) δ 8.21 (d, 1H), 8.04 (d, 1H),7.89 (dd, 1H), 7.74 (d, 2H), 7.57-7.64 (m, 3H), 6.94 (dd, 1H), 4.60(quint, 1H), 1.40 (d, 6H), 1.30 (s, 9H); MS (ES) (M+H)⁺ expected 502.1,found 502.1.

Example 346:N-{2-[(6-Amino-pyridin-3-yl)-hydroxyimino-methyl]-5-chloro-pyridin-3-yl}-4-tert-butyl-benzenesulfonamide

Following the procedure for 342,N-[2-(6-amino-pyridine-3-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide(15 mg, 0.034 mmol) was converted to its corresponding hydroxime: (Lesspolar isomer)¹H NMR (400 MHz, CD₃OD) δ 8.20 (d, 1H), 8.06 (d, 1H), 7.87(dd, 1H), 7.71 (d, 2H), 7.51-7.58 (m, 3H), 6.92 (dd, 1H), 1.29 (s, 9H);MS (ES) [M+H]+ expected 460.1, found 460.0.

Example 347:3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylicacid (2-fluoro-phenyl)-methyl-amide

3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylicacid (75 mg, 0.20 mmol), (2-fluoro-phenyl)-methyl-amine (23 mg, 0.61mmol), HATU (193 mg, 0.51 mmol), TEA (114 μL, 0.81 mmol) and 0.5 mL NMPwere combined in a 4 mL vial and stirred overnight at 60° C. HPLCpurification (10 to 95% gradient of MeCN-water) provided3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carboxylicacid (2-fluoro-phenyl)-methyl-amide: ¹H NMR (400 MHz, CDCl₃) 9.98 (s,1H), 8.01 (s, 1H), 7.82 (d, 2H), 7.63 (s, 1H), 7.51 (d, 2H), 7.13 (m,1H), 6.92 (t, 1H), 6.84 (t, 1H), 6.37 (m, 1H), 3.38 (t, 3H), 1.26 (s,9H); MS m/z 476.1.

Example 348:4-tert-Butyl-N-[5-chloro-2-(6-cyano-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamide

4-tert-Butyl-N-[5-chloro-2-(6-fluoro-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamidewas prepared fromN-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamideand 6-fluoro-pyridine-3-carbaldehyde using the procedure described inexamples 35 and 36.

4-tert-Butyl-N-[5-chloro-2-(6-fluoro-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamide(444 mg, 0.899 mmol) was dissolved in DMF (5 mL). KCN (300 mg, 4.6 mmol)was then added and the reaction mixture was heated to 60° C. for 2hours. Additional KCN (110 mg, 1.7 mmol) was then added and the reactionwas stirred for another 2 hours. The solvent was removed under reducedpressure and the resulting brown oil purified by column (1:4EtOAc/hexanes) to give 172 mg (0.345 mmol, 38% yield). MS calc'd forC₂₄H₂₄ClN₄O₄S (MH⁺): 499.1, found 499.1.

Example 349:4-tert-Butyl-N-[5-chloro-2-(6-cyano-pyridine-3-carbonyl)-pyridin-3-yl]-benzenesulfonamide

4-tert-Butyl-N-[5-chloro-2-(6-cyano-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-benzenesulfonamide(15 mg, 0.030 mmol) was dissolved in 4N HCl (500

L) and dioxane (1 mL). The reaction was then stirred at 90° C. for 12hours. The solvent was removed under reduced pressure and the crudesolid was purified by preparatory TLC (1:4 EtOAc/hexanes) to give 5 mg(0.01 mmol, 40% yield) of the desired product as a white solid. MScalc'd for C₂₂H₂₀ClN₄O₃S (MH⁺): expected 455.1, found 455.0.

Example 350: 6-Fluoro-pyridine-2-carboxylic Acid methoxy-methyl-amide

To a cooled mixture of 6-fluoro picolinic acid (1.19 g, 8.43 mmol),N,O-dimethylhydroxyl amine (860 mg, 8.82 mmol) and Et₃N (3.27 mL, 23.52mmol) in CH₂Cl₂ (10 mL) was added 1-propane phosphonic acid cyclicanhydride (4.49 mL, 7.05 mmol; 50 wt % solution in EtOAc) dropwise andstirred at room temperature for 3 h. The reaction mixture was filtered,washed with CH₂Cl₂ (2×10 mL), evaporated to dryness, and subjected tocolumn chromatography (SiO₂, 40% EtOAc-hexanes) to obtain6-fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide (1.19 g) in 73%yield. ESMS m/z (relative intensity): 185 (M+H)⁺ (100).

Example 351: 6-Azido-pyridine-2-carboxylic Acid methoxy-methyl-amide

A mixture of 6-fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide(1.19 g, 6.47 mmol) and azido-trimethylsilane (2.0 g, 16.8 mmol) in DMF(10 mL) was stirred at 110° C. for 72 h. The reaction mixture wasdiluted with 50 mL of dichloromethane and washed with water (3×50 mL).The organic layer was separated, evaporated to dryness, and subjected tocolumn chromatography (SiO₂, 40% EtOAc-hexanes) to obtain6-azido-pyridine-2-carboxylic acid methoxy-methyl-amide (0.335 g) in 25%yield. ESMS m/z (relative intensity): 208 (M+H)⁺ (100).

Example 352:N-[2-(6-Azido-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-N-methoxymethyl-benzenesulfonamide

N-[2-(6-Azido-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-N-methoxymethyl-benzenesulfonamidewas prepared fromN-(2-bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide according to previously described procedure in example 29,step 1. The product was purified by flash column chromatography onsilica gel using ethyl acetate-hexane. MS m/z: 515.1 (M+H)⁺.

Example 353:N-[2-(6-Amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-N-methoxymethyl-benzenesulfonamide

To a mixture ofN-[2-(6-azido-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(0.3 mmol, 155 mg) in THF (3 mL) was added3-[bis-(2-carboxy-ethyl)-phosphanyl]-propionic acid (1 mmol, 250 mg).The mixture was stirred at 50° C. for 3 h. Upon completion of thereduction, the THF was removed under reduced pressure. The residue wasdiluted with EtOAc and the organics were washed with saturated sodiumbicarbonate, dried with sodium sulfate, concentrated in vacuo, andpurified via automated silica gel chromatography to generate the desiredproduct. MS m/z: 489.1 (M+H)⁺.

Example 354:N-[2-(6-Amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide

A mixture ofN-[2-(6-amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-N-methoxymethyl-benzenesulfonamide(58.6 mg, 1.03 mmol) in 4N HCl in dioxane (4 mL) and water (1 mL) wasstirred at 90° C. overnight. The reaction mixture was cooled to roomtemperature, evaporated to dryness, and treated with saturated aqueousNaHCO₃ solution until pH 7-8. The mixture was extracted with EtOAc (2×25mL), dried (anhydrous Na₂SO₄), and concentrated in vacuo. The obtainedresidue was purified via column chromatography (SiO₂, 70% EtOAc inhexanes) to affordN-[2-(6-amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide(34.5 mg) in 64% yield. ¹H NMR (400 MHz, CDCl₃) δ11.1 (s, 1H), 8.26 (d,1H), 8.18 (d, 1H), 7.76 (d, 2H), 7.51 (t, 1H), 7.44 (d, 2H), 7.03 (d,1H), 6.66 (d, 1H), 4.67 (s, 2H), 1.22 (s, 9H); ESMS m/z (relativeintensity): 445.1 (M+H)⁺ (100).

Example 355:N-{6-[3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carbonyl]-pyridin-2-yl}-acetamide

N-[2-(6-Amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide(26 mg, 0.05 mmol) in THF (2 mL) was treated with TMS-isocyanate (100mg) and AcOH (0.5 mL), and then stirred at 80° C. for 2 h. The mixturewas subsequently diluted with acetonitrile (1 mL) and purified via HPLCto afford the title compound: ¹H NMR (400 MHz, CDCl₃) δ 11.1 (S, 1H),8.48 (d, 1H), 8.32 (d, 1H), 8.24 (m, 2H), 7.86 (m, 3H), 7.55 (d, 2H),5.30 (s, 2H), 4.75 (s, 2H), 1.22 (s, 9H); ESMS m/z (relative intensity):488.1 (M+H)⁺ (100).

Example 356:4-tert-Butyl-N-[5-chloro-2-(6-methanesulfonylamino-pyridine-2-carbonyl)-pyridin-3-yl]-benzenesulfonamide

N-[2-(6-Amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide(52 mg, 0.1 mmol) in pyridine was treated with methanesulfonyl chloride(100 mg) and then stirred at 70° C. for 2 h. After evaporation ofsolvent under reduced pressure, to the mixture was added THF (5 mL),followed by NaOH (2N, 2 mL) and stirred at room temperature for another2 h. The mixture was dissolved in EtOAc and washed with 1N HCl, NaHCO₃(saturated), brine, dried over MgSO₄, concentrated under reducedpressure, and purified through automated normal-phase chromatography toafford the title compound: 1H NMR (400 MHz, CDCl₃) δ 11.0 (s, 1H), 8.37(d, 1H), 8.25 (d, 1H), 7.82 (d, 2H), 7.72 (m, 1H), 7.61 (d, 1H), 7.42(d, 2H), 7.17 (d, 1H), 3.15 (s, 3H), 1.23 (s, 9H); MS (ES) [M+H]+expected 523.1, found 523.1.

Example 357:N-{6-[3-(4-tert-Butyl-benzenesulfonylamino)-5-chloro-pyridine-2-carbonyl]-pyridin-2-yl}-acetamide

N-[2-(6-amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide(52 mg, 0.1 mmol) in pyridine/1,4-dioxane (1:1, 4 mL) was treated withacetyl chloride (100 mg) and then stirred at 60° C. for 2 h. Afterevaporation of solvent under reduced pressure, to the mixture was addedTHF (5 mL), followed by NaOH (2N, 2 mL) and stirred at room temperaturefor another 2 h. The mixture was diluted with EtOAc and the organicswere washed with 1N HCl, NaHCO₃ (saturated), and brine; dried overMgSO₄, concentrated under reduced pressure, and purified throughautomated normal-phase chromatography to afford the title compound: ¹HNMR (400 MHz, CDCl₃) δ 10.80 (s, 1H), 8.37 (d, 1H), 8.22 (m, 2H), 8.14(s, 1H), 7.80 (m, 3H), 7.46 (m, 3H), 2.20 (s, 3H), 1.23 (s, 9H); MS (ES)[M+H]+ expected 487.1, found 487.1.

Example 358: Preparation of(3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanone

Step 1: (2-Bromo-5-chloro-pyridin-3-yl)-(4-methoxy-benzyl)-amine

5.16 g (24.8 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine, 7.09 g (52.1mmol) of p-anisaldehyde and 13.1 g (62.0 mmol) of sodiumtriacetoxyborohydride were dissolved in 100 mL of DCM and stirred atr.t. overnight. The next day DCM was replaced with chloroform, 5 gexcess of sodium triacetoxyborohydride and 3 g excess of p-anisaldehydewere added and the reaction was conducted at 65° C. for 3 h. The mixturewas worked up with aqueous sodium bicarbonate and purified on silicafollowed by recrystallization from ethyl acetate/hexanes mixture to give3.40 g (42%) of the product as a white solid. MS (M+H)/z=328.9.

Step 2

(2-Bromo-5-chloro-pyridin-3-yl)-(4-methoxy-benzyl)-carbamic acidtert-butyl ester: 2.19 g (6.66 mmol) of(2-bromo-5-chloro-pyridin-3-yl)-(4-methoxy-benzyl)-amine, 2.90 g (13.3mmol) of di-tert-butyl dicarbonate and 82 mg (0.67 mmol) of DMAP weredissolved in 5 mL of DCM and heated to 60° C. letting DCM to evaporate.After 1 h 5 g of di-tert-butyl dicarbonate were added and the mixturestirred at 80° C. for 30 minutes. Flash chromatography of such mixtureafforded 2.7 g (95%) of the product as a white solid. LC-MSD, m/z forC₁₈H₂₀BrClN₂O₃ [M+H]+=426.9, 428.9, 430.9.

Step 3

(2-{[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-hydroxy-methyl}-5-chloro-pyridin-3-yl)-(4-methoxy-benzyl)-carbamicacid tert-butyl ester: 2.12 g (4.96 mmol) of(2-bromo-5-chloro-pyridin-3-yl)-(4-methoxy-benzyl)-carbamic acidtert-butyl ester were dissolved in 12 mL THF and cooled down undernitrogen atmosphere to 0° C. 5.2 mL of 2M solution of isopropylmagnesiumchloride solution in THF were added dropwise. Stirring at 0° C. for 15minutes resulted in a complete bromine-magnesium exchange. The solutionwas cooled down to −20° C. and 1.29 g (4.96 mmol) of solid1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehydewas added. After 5 minutes the mixture was allowed to warm up to r.t.and was stirred at r.t. for 1 h. Aqueous ammonium chloride solution wasadded and the mixture was extracted with DCM. Organic layer wasevaporated under reduced pressure. Flash chromatography on silica using5-60% ethyl acetate in hexanes afforded 1.76 g (58%) of the product as awhite solid. LC-MSD, m/z for C₃₂H₄₁ClN₄O₄Si [M+H]+=609.2, 611.2.

Step 4

{2-[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl]-5-chloro-pyridin-3-yl}-(4-methoxy-benzyl)-carbamicacid tert-butyl ester: 1.76 g (2.89 mmol) of(2-{[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-hydroxy-methyl}-5-chloro-pyridin-3-yl)-(4-methoxy-benzyl)-carbamicacid tert-butyl ester and 3.08 g (7.22 mmol) of Dess-Martin periodinanewere dissolved in 10 mL of DCM and stirred at r.t. for 2 h. The reactionwas worked up with aqueous sodium bicarbonate and sodium thiosulfatefollowed by purification on silica with 0-50% ethyl acetate in hexanesto afford 0.97 g of a mixture of the expected product and itsdesilylated analog as a yellow solid. LC-MSD, m/z for C₃₂H₃₉ClN₄O₄Si[M+H]+=607.2, 609.2;

Step 5

(3-Amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanone:0.97 g of{2-[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl]-5-chloro-pyridin-3-yl}-(4-methoxy-benzyl)-carbamicacid tert-butyl ester and desilylated analog mixture was dissolved in 5mL of TFA, stirred at r.t. for 2 h and evaporated. The residue waspartitioned into a mixture of aqueous sodium bicarbonate solution andethyl acetate. The organic layer was evaporated under reduced pressure.The solid residue was triturated with 200 mL of a 1:3 mixture of ethylacetate-hexanes to afford 372 mg of the product as a brown solid.LC-MSD, m/z for C₁₃H₉ClN₄O [M+H]+=273.0, 275.0;

Example 359: 1-Chloro-2-(1,1-difluoro-ethyl)-4-nitro-benzene

650 mg (3.27 mmol) of 1-(2-chloro-5-nitro-phenyl)-ethanone was combinedwith 855 μL (6.54 mmol) of DAST (diethylaminosulfur trifluoride) andheated to 50° C. for 5 h. The mixture was cooled down and diluted with50 mL DCM. The solution was washed with 10 mL of water. The organiclayer was evaporated on silica and purified on silica gel eluting with a0-20% ethyl acetate in hexanes to give 490 mg (68%) of the pure productas a white solid. LC-MSD spectrum not observed;

Example 360: 4-Chloro-3-(1,1-difluoro-ethyl)-phenylamine

480 mg (2.17 mmol) of 1-chloro-2-(1,1-difluoro-ethyl)-4-nitro-benzene,464 mg (8.67 mmol) of ammonium chloride and 365 mg (6.51 mmol) of ironpowder were added to a mixture of 1.5 mL of water and 3 mL of methanol.The slurry was stirred at 70° C. for 1 h, and then cooled down, filteredthrough a pad of celite washing with excess methanol and concentrateddown under reduced pressure. The residue was dissolved in ethyl acetate,evaporated under reduced pressure on silica gel and purified on silicaeluting with a 5-30% ethyl acetate in hexanes to give 365 mg of the pureproduct as a white solid. LC-MSD, m/z for C₈H₈ClF₂N [M+H]+=192.0, 194.0;

Example 361: 1-(5-Amino-2-chloro-phenyl)-ethanone

2.01 g (10.1 mmol) of 1-(2-chloro-5-nitro-phenyl)-ethanone, 2.54 g (47.5mmol) of ammonium chloride and 1.99 g (35.7 mmol) of iron powder wereadded to a mixture of 6 mL of water and 12 mL of methanol. The slurrywas stirred at 70° C. for 1 h, and then cooled down, filtered through apad of celite and concentrated down under reduced pressure. The residuewas taken up in 60 mL ethyl acetate and 60 mL of water. The aqueouslayer was extracted with 40 mL of ethyl acetate and the combined organiclayers were evaporated under reduced pressure. The residue was filteredthrough a pad of silica gel eluting with a 7:3 mixture of ethylacetate-hexanes to give 1.6 g (94%) of the pure product as a whitesolid. LC-MSD, m/z for C₈H₈ClNO [M+H]+=170.0, 172.0;

Example 362: General Procedure for Para-Chlorination of Anilines

Aniline (23 mmol) is dissolved in 100 mL of isopropanol and 23 mmol ofNCS is added in one portion. After 30 minutes of stirring at r.t. silicagel is added and the solution is evaporated under reduced pressure.Flash chromatography using ethyl acetate/hexanes affords the product.

Example 363: 3-tert-Butyl-4-chloro-phenylamine

Prepared from 3.48 g of 3-tert-butyl-phenylamine and 3.12 g NCS. Yield:1.5 g. LC-MSD, m/z for C₁₀H₁₄ClN [M+H]+=184.1, 186.1;

Example 364: 4-Chloro-3-iso-propyl-phenylamine

Prepared from 7.84 g of 3-iso-propyl-phenylamine and 7.75 g NCS. Yield:4.6 g. LC-MSD, m/z for C₉H₁₂ClN [M+H]+=170.2, 172.0;

Example 365: 4-Chloro-3-ethyl-phenylamine

Prepared from 7.36 g of 3-ethyl-phenylamine and 8.12 g NCS. Yield: 4.4g. LC-MSD, m/z for C₈H₁₀ClN [M+H]+=156.0, 158.0;

Example 366: 4-Ethyl-3-trifluoromethyl-phenylamine

6.52 g (27.2 mmol) of 4-bromo-3-trifluoromethyl-phenylamine wasdissolved in 30 mL of diethylamine in a sealed tube. To this solutionsequentially were added 5.32 g (54.4 mmol) of trimethylsilylacetylene,382 mg (0.54 mmol) of bis(triphenylphosphine)dichloropalladium(II) and103 mg (0.54 mmol) of copper(I) iodide. The vessel was flushed withnitrogen, sealed and heated to 120° C. for 2 days. The solution wasevaporated under reduced pressure, redissolved in DCM and evaporated onsilica gel. Flash chromatography on silica using 0-40% ethyl acetate inhexanes afforded a mixture of3-trifluoromethyl-4-trimethylsilanylethynyl-phenylamine and startingmaterial. The mixture was dissolved in 30 mL methanol and heated to 60°C. for 30 minutes with 5 g of potassium carbonate. To this silica gelwas added and the solvent was evaporated under reduced pressure. Flashchromatography on silica using 10-50% ethyl acetate in hexanes afforded2.85 g of a mixture of 4-ethynyl-3-trifluoromethyl-phenylamine and4-bromo-3-trifluoromethyl-phenylamine. It was dissolved in 50 mL ofmethanol, followed by the addition of 220 mg of 10% wet palladium oncarbon catalyst and reduction under atmospheric pressure of hydrogen gasat r.t. for 16 h. To this mixture 10 mL of 2M ammonia solution inmethanol was added, followed by silica gel, and it was evaporated underreduced pressure. Flash chromatography on silica using 5-30% ethylacetate in hexanes afforded 1.45 g of the product as a white solid.LC-MSD, m/z for C₉H₁₀F₃N [M+H]+=190.1;

Example 367: General Procedure for Conversion of Anilines to SulfonylChlorides

Followed the procedure described in Org. Syn. Coll. Vol. 7 p. 508. Flashchromatography using ethyl acetate in hexanes affords the product.

Example 368: 3-tert-Butyl-4-chloro-benzenesulfonyl Chloride

Amounts used: 10 mL of acetic acid was saturated with sulfur dioxide,220 mg of copper(I) chloride, 1.5 g (8.20 mmol) of3-tert-butyl-4-chloro-phenylamine dissolved in a mixture of 3 mL ofacetic acid and 3 mL of concentrated hydrochloric acid, 0.622 g ofsodium nitrite in 3 mL of water. Flash chromatography on silica using0-15% ethyl acetate in hexanes afforded 0.42 g of the product as a whitesolid. LC-MSD spectrum not observed.

Example 369: 4-Chloro-3-iso-propyl-benzenesulfonyl Chloride

Amounts used: 25 mL of acetic acid was saturated with sulfur dioxide,671 mg of copper(I) chloride, 4.60 g (27.1 mmol) of4-chloro-3-isopropyl-phenylamine dissolved in a mixture of 4 mL ofacetic acid and 9 mL of concentrated hydrochloric acid, 2.3 g of sodiumnitrite in 10 mL of water. Flash chromatography on silica using 3-20%ethyl acetate in hexanes afforded 2.18 g of the product as a whitesolid. LC-MSD spectrum not observed.

Example 370: 4-Chloro-3-ethyl-benzenesulfonyl Chloride

Amounts used: 25 mL of acetic acid was saturated with sulfur dioxide,700 mg of copper(I) chloride, 4.40 g (28.3 mmol) of4-chloro-3-ethyl-phenylamine dissolved in a mixture of 9 mL of aceticacid and 9 mL of concentrated hydrochloric acid, 2.20 g of sodiumnitrite in 10 mL of water. Flash chromatography on silica using 0-20%ethyl acetate in hexanes afforded 3.4 g of the product as a white solid.LC-MSD spectrum not observed;

Example 371: 3-Acetyl-4-chloro-benzenesulfonyl Chloride

Amounts used: 8 mL of acetic acid was saturated with sulfur dioxide, 233mg of copper(I) chloride, 1.60 g (9.41 mmol) of1-(5-amino-2-chloro-phenyl)-ethanone dissolved in a mixture of 3 mL ofacetic acid and 3 mL of concentrated hydrochloric acid, 714 mg of sodiumnitrite in 3 mL of water. Flash chromatography on silica using 20-50%ethyl acetate in hexanes afforded 1.6 g of the product as a white solid.LC-MSD, m/z for C₈H₆Cl₂O₃S [M+H]+=252.9, 254.9, 256.9;

Example 372: 4-Chloro-3-(1,1-difluoro-ethyl)-benzenesulfonyl Chloride

Amounts used: 2 mL of acetic acid was saturated with sulfur dioxide, 47mg of copper(I) chloride, 365 mg (1.91 mmol) of4-chloro-3-(1,1-difluoro-ethyl)-phenylamine dissolved in a mixture of1.2 mL of acetic acid and 0.6 mL of concentrated hydrochloric acid, 145mg of sodium nitrite in 1 mL of water. Flash chromatography on silicausing 0-15% ethyl acetate in hexanes afforded 377 mg of the product as awhite solid. LC-MSD spectrum not observed;

Example 373: 4-Ethyl-3-trifluoromethyl-benzenesulfonyl Chloride

Amounts used: 8 mL of acetic acid was saturated with sulfur dioxide, 190mg of copper(I) chloride, 1.45 g (7.67 mmol) of4-ethyl-3-trifluoromethyl-phenylamine dissolved in a mixture of 3 mL ofacetic acid and 3 mL of concentrated hydrochloric acid, 0.635 g ofsodium nitrite in 3 mL of water. Flash chromatography on silica using0-20% ethyl acetate in hexanes afforded 0.9 g of the product as a whitesolid. LC-MSD spectrum not observed; HPLC retention time: 2.9 min.

Example 374: General Procedure for the Preparation of Sulfonamideswithout the Azaindole Moiety

Sulfonyl chloride (1 eqiuv.) and amine (1.1 equiv.) are dissolved inpyridine and heated to 80° C. overnight. The solvent is evaporated underreduced pressure and the residue purified by flash chromatography toproduce the sulfonamide.

Example 375: General Procedure for the Preparation of Sulfonamides withthe Azaindole Moiety

Sulfonyl chloride (3.5 eqiuv.) and amine (1 equiv.) are dissolved inpyridine and heated to 80° C. overnight. The temperature is lowered to65° C. and methanol and aqueous sodium hydroxide solution are added andthe mixture is stirred for 30 minutes. The solvent is evaporated underreduced pressure and the residue purified by reverse-phase HPLC followedby flash chromatography to produce the sulfonamide.

Example 376:N-(2-Bromo-5-chloro-pyridin-3-yl)-4-ethyl-3-trifluoromethyl-benzenesulfonamide

Prepared from 1.04 g (3.82 mmol) of4-ethyl-3-trifluoromethyl-benzenesulfonyl chloride and 0.87 g (4.20mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in 3 mL pyridine usingprocedure x. Yield: 0.45 g of a white solid. LC-MSD, m/z forC₁₄H₁₁BrClF₃N₂O₂S [M+H]+=442.9, 444.9, 446.9.

Example 377:N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-3-ethyl-benzenesulfonamide

Prepared from 1.71 g (7.15 mmol) of 4-chloro-3-ethyl-benzenesulfonylchloride and 1.34 g (6.47 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in4 mL pyridine using procedure x. Yield: 2.35 g of a white solid. LC-MSD,m/z for C₁₃H₁₁BrCl₂N₂O₂S [M+H]+=408.8, 410.8, 412.8.

Example 378:N-(2-Bromo-5-chloro-pyridin-3-yl)-3-tert-butyl-4-chloro-benzenesulfonamide

Prepared from 420 mg (1.57 mmol) of3-tert-butyl-4-chloro-benzenesulfonyl chloride and 326 mg (1.57 mmol) of2-bromo-5-chloro-pyridin-3-ylamine in 3 mL pyridine using procedure x.Yield: 0.48 g of a white solid. LC-MSD, m/z for C₁₅H₁₅BrCl₂N₂O₂S[M+H]+=436.9, 438.8, 440.8.

Example 379:3-Acetyl-N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-benzenesulfonamide

Prepared from 1.6 g (6.32 mmol) of 3-acetyl-4-chloro-benzenesulfonylchloride and 1.3 g (6.28 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in8 mL pyridine using procedure x. Yield: 1.3 g of a white solid. LC-MSD,m/z for C₁₃H₉BrCl₂N₂O₃S [M+H]+=422.8, 424.8, 426.8.

Example 380:N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1,1-difluoro-ethyl)-benzenesulfonamide

Prepared from 377 mg (1.37 mmol) of4-chloro-3-(1,1-difluoro-ethyl)-benzenesulfonyl chloride and 270 mg(1.30 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine in 2 mL pyridine usingprocedure x. Yield: 460 mg of a white solid. LC-MSD, m/z forC₁₃H₉BrCl₂F₂N₂O₂S [M+H]+=444.8, 446.8, 448.8.

Example 381:N-(2-Cyano-5-methyl-pyridin-3-yl)-4-methyl-3-trifluoromethyl-benzenesulfonamide

Prepared from 2.92 g (11.3 mmol) of4-methyl-3-trifluoromethyl-benzenesulfonyl chloride and 1.25 g (9.41mmol) of 3-amino-5-methyl-pyridine-2-carbonitrile in 4 mL pyridine usingprocedure x. Yield: 1.13 g of a white solid. LC-MSD, m/z forC₁₅H₁₂F₃N₃O₂S [M+H]+=356.0.

Example 382:3,4-Dichloro-N-(2-cyano-5-methyl-pyridin-3-yl)-benzenesulfonamide sodiumsalt

Prepared from 2.00 g (8.15 mmol) of 3,4-dichloro-benzenesulfonylchloride and 903 mg (6.79 mmol) of3-amino-5-methyl-pyridine-2-carbonitrile in 4 mL pyridine usingprocedure x. Thus obtained compound was dissolved in a mixture of 20 mLTHF and 10 mL of water with 326 mg (8.15 mmol) of sodium hydroxide andstirred at r.t. for 1 h, then evaporated under reduced pressure todryness and washed with 10 mL of water. The solid was dried under vacuumat 110° C. Yield: 1.34 g of a white solid. LC-MSD, m/z forC₁₃H₁₀Cl₂N₃O₂S [M+H]+=341.9, 343.9.

Example 383:N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1-hydroxy-1-methyl-ethyl)-benzenesulfonamide

365 mg (0.86 mmol) of3-acetyl-N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-benzenesulfonamidewas dissolved in 3 mL of anhydrous THF and cooled down under nitrogenatmosphere to −78° C. To that solution 0.86 mL of 3M methylmagnesiumbromide solution in diethyl ether was added dropwise. The solution wasallowed to warm up to 0° C. and was then quenched with aqueous ammoniumchloride and extracted with DCM. The organic layer was evaporated underreduced pressure and purified on silica using 5-40% ethyl acetate inhexanes to yield 288 mg of a white solid. LC-MSD, m/z forC₁₄H₁₃BrCl₂N₂O₃S [M+H]+=438.9, 440.9, 442.9.

Example 384: General Procedure for the Protection of Sulfonamides

Sulfonamide (1 eqiuv.) and methoxymethyl chloride (2.5 equiv.) aredissolved in THF, 3 equiv. of potassium carbonate are added and themixture is stirred overnight at r.t. The solvent is evaporated underreduced pressure and the residue purified by flash chromatography toproduce the MOM-protected sulfonamide.

Example 385:N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-3-ethyl-N-methoxymethyl-benzenesulfonamide

Prepared from 2.35 g (5.73 mmol) ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-ethyl-benzenesulfonamide,2.76 g of potassium carbonate and 1.3 mL of methoxymethyl chloride in 10mL THF using procedure x. Yield: 980 mg of a white solid. LC-MSD, m/zfor C₁₅H₁₅BrCl₂N₂O₃S [M+H]+=452.9, 454.9, 456.9.

Example 386:N-(2-Bromo-5-chloro-pyridin-3-yl)-3-tert-butyl-4-chloro-N-methoxymethyl-benzenesulfonamide

Prepared from 480 mg (1.10 mmol) ofN-(2-bromo-5-chloro-pyridin-3-yl)-3-tert-butyl-4-chloro-benzenesulfonamide,400 mg of potassium carbonate and 170 μL (1.57 mmol) of methoxymethylchloride in 2 mL THF using procedure x. Yield: 160 mg of a white solid.LC-MSD, m/z for C₁₇H₁₉BrCl₂N₂O₃S [M+H]+=480.9, 482.9, 484.9.

Example 387:N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1-hydroxy-1-methyl-ethyl)-N-methoxymethyl-benzenesulfonamide

Prepared from 285 mg (0.648 mmol) ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1-hydroxy-1-methyl-ethyl)-benzenesulfonamide,268 mg of potassium carbonate and 150 μL of methoxymethyl chloride in 2mL THF using procedure x. Yield: 153 mg of a white solid. LC-MSD, m/zfor C₁₆H₁₇BrCl₂N₂O₄S [M+H]+=482.9, 484.9, 486.9.

Example 388:N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1,1-difluoro-ethyl)-N-methoxymethyl-benzenesulfonamide

Prepared from 460 mg (1.03 mmol) ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1,1-difluoro-ethyl)-benzenesulfonamide,355 mg of potassium carbonate and 195 μL of methoxymethyl chloride in 2mL THF using procedure x. Yield: 162 mg of a white solid. LC-MSD, m/zfor C₁₅H₁₃BrCl₂F₂N₂O₃S [M+H]+=488.8, 490.8, 492.8; HPLC retention time:2.9 min.

Example 389: General Procedure for the Preparation ofN-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-arylsulfonamidesfrom N-(2-Bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-arylsulfonamides

Step 1

N-(2-{[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-hydroxy-methyl}-5-chloro-pyridin-3-yl)-N-methoxymethyl-arylsulfonamide:1 mmol ofN-(2-bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-arylsulfonamide wasdissolved under nitrogen atmosphere in 3 mL THF. 1.05 mL of 2M solutionof isopropylmagnesium chloride solution in THF was added dropwise.Stirring at r.t. for 15 minutes resulted in a complete bromine-magnesiumexchange. The solution was cooled down to −20° C. and 1.1 mmol of solid1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehydewas added. After 5 minutes the mixture was allowed to warm up to r.t.and was stirred at r.t. for 1 h. Aqueous ammonium chloride solution wasadded and the mixture was extracted with DCM. Organic layer wasevaporated under reduced pressure. Flash chromatography on silica usingethyl acetate in hexanes afforded the products.

Step 2

N-{2-[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl]-5-chloro-pyridin-3-yl}-N-methoxymethyl-arylsulfonamide:1 mmol ofN-(2-{[1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-hydroxy-methyl}-5-chloro-pyridin-3-yl)-N-methoxymethyl-arylsulfonamideand 2.5 mmol of Dess-Martin periodinane were dissolved in 1 mL of DCMand stirred at r.t. for 2 h. The reaction was worked up with aqueoussodium bicarbonate and sodium thiosulfate and purified on silica withethyl acetate in hexanes to afford a mixture of the expected product andits desilylated analog as a yellow solid.

Step 3

N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-arylsulfonamide:1 mmol ofN-{2-[1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl]-5-chloro-pyridin-3-yl}-N-methoxymethyl-arylsulfonamidemixture with its desilylated analog was dissolved in a mixture of 20 mLof methanol and 20 mL of 6N hydrochloric acid. The solution was heatedin a sealed tube at 80° C. for 8 h, then cooled down and evaporated. Theresidue was dissolved in methanolic ammonia and evaporated on silica gelunder reduced pressure. Flash chromatography on silica using ethylacetate in hexanes afforded the products as yellow solids. In some casesadditional reverse-phase HPLC purification step was necessary to obtainpure products.

Example 390: 1 H-Pyrrolo[2,3-b]pyridine-4-boronic Acid

199 mg (0.816 mmol) of 4-iodo-1H-pyrrolo[2,3-b]pyridine, 203 mg (0.897mmol) of bis(neopentyl glycolato)diboron, 240 mg (2.45 mmol) ofpotassium acetate and 20 mg (0.024 mmol) ofbis(triphenylphosphine)dichloropalladium(II) were dissolved/suspended in1 mL of DMSO and reacted at 90° C. for 4 h. The mixture was separatedusing reverse-phase HPLC to give 140 mg of a mixture of the desiredboronic acid, its neopentyl glycolate and 1H-pyrrolo[2,3-b]pyridine.LC-MSD, m/z for C₇H₇BN₂O₂ [M+H]+=162.1, 163.0 (boronic acid). LC-MSD,m/z for C₁₂H₁₅BN₂O₂ [M+H]+=230.1, 231.0; HPLC retention time: 0.2 min(boronic ester). LC-MSD, m/z for C₇H₆N₂ [M+H]+=119.0.

Example 391:4-Chloro-2-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-benzoicAcid

To a solution of Na₂CO₃ (11.7 g, 110.7 mmol) in water (50 mL) and1,4-dioxane (50 mL) at 60° C. was added 2-amino-4-chloro-benzoic acid(5.0 g, 29.14 mmol) followed by4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (20.15 g, 72.48mmol) in 3 portions and heated the resulting reaction mixture at 80° C.for 4 h. 2N HCl Was added until the reaction mixture became acidic(pH=˜2) and obtained white solid was filtered, washed with water, driedunder high vacuum to obtain title compound (7.8 g) in 65% yield. MS (ES)M+Na expected 436.0, found 435.8.

Example 392:4-Chloro-2-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-N-methoxy-N-methyl-benzamide

To a solution of4-chloro-2-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-benzoicacid (5.0 g, 12.1 mmol) in THF (20 mL) was addedN,N′-carbonyldiimidazole (CDI, 2.45 g, 15.13 mmol) in portions(Caution!: CO₂). The resulting reaction mixture was then heated atreflux. After 4 hours, reaction mixture was cooled to room temperatureand charged with N,O-dimethylhydroxylamine hydrochloride (1.3 g, 13.31mmol) and heated at reflux for 1 hour. Water (100 mL) was added followedby EtOAc (100 mL) with stirring. EtOAc layer was separated and aqueouslayer was further extracted with EtOAc (2×50 mL). Combined EtOAc layerswere washed with aq. 2N HCl (50 mL), saturated NaHCO₃ solution (50 mL),brine (50 mL), dried (Na₂SO₄) and evaporated. Obtained crude product waspurified by automated normal-phase chromatography (50% EtOAc in hexanes)to afford title compound (4.0 g) in 73% yield. MS (ES) M+H expected457.0, found 456.9.

Example 393:4-chloro-N-(5-chloro-2-formyl-phenyl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

Diisobutylaluminium hydride (DIBAL-H, 1.5M solution in toluene, 0.73 mL,1.1 mmol) was added drop wise to a solution of4-chloro-2-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-N-methoxy-N-methyl-benzamide(220 mg, 0.44 mmol) in THF (3 mL) at −78° C. and stirred at the sametemperature for an hour. Saturated aqueous sodium potassium tartaratesolution (10 mL) was added slowly, warmed to room temperature, extractedwith EtOAc (2×25 mL), dried (anhydrous Na₂SO₄) and concentrated.Obtained residue was purified by column chromatography (SiO₂, 50%EtOAc-hexanes) to obtain4-chloro-N-(5-chloro-2-formyl-phenyl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (120 mg) in 62% yield. ESMS m/z (relative intensity): 410(M−31)⁺ (95), 464 (M+Na)⁺ (100).

Example 394: 2-Bromo-5-methyl-3-nitropyridine

POBr₃ (222.8 g, 0.78 mol) was added in portions to2-hydroxy-5-methyl-3-nitropyridine (100 g, 0.65 mol) in DMF (500 mL)with stirring at 0-10° C. then the reaction mixture was stirred at 80°C. under nitrogen for 12 h. Reaction mixture was cooled and poured intocrushed ice (1 Kg), obtained solid was filtered, washed thoroughly withice-cold water (2×500 mL), dried in a desiccator under high vacuum forone day to obtain 2-bromo-5-methyl-3-nitropyridine as yellow solid (121g) in 86% yield. (M+H) Expected: 217; found 216.9.

Example 395: 2-Cyano-5-methyl-3-nitropyridine

A round bottom flask was charged with 2-bromo-5-methyl-3-nitropyridine(60.53 g, 278.9 mmol) and CuCN (27.52 g, 307.3 mmol) The flask wasevacuated, and back-filled with nitrogen. DMF (150 mL) was added viacannula. The solution was heated to 70° C. for 1.5 h. After cooling toroom temperature, the reaction mixture was poured into EtOAc (500 mL)and water (250 mL). Both phases were filtered through a 1 cm bed ofcelite. The layers were separated, and the organic phase washed withwater (2×100 mL) then with a solution of 1:1 sat. aq. NH₄Cl/NH₄OH (2×100mL). The combined aqueous layers were extracted with EtOAc (2×200 mL).The combined organic layers were dried over MgSO₄ and concentrated invacuo to afford the title compound (36.10 g, 79% yield).

Example 396: 3-Amino-2-cyano-5-methylpyridine

To acetic acid (300 mL) in a 3-neck 2 liter round bottom flask equippedwith mechanical stirrer and a thermometer was added Fe powder (99.6 g,1.78 mol) with stirring at 60° C. 2-Cyano-5-methyl-3-nitropyridine (97g, 0.59 mol) was dissolved in acetic acid (400 mL) with gentle warmingand added to the above reaction mixture drop wise with efficientstirring so that the reaction temperature kept below 80° C. over 3.5hours. The reaction mixture was further stirred for an addition 30 min,cooled, diluted with EtOAc (750 mL), filtered through celite and washedwith EtOAc (1×500 mL, 3×250 mL). Combined EtOAc layers were evaporatedto dryness to obtain dark brown solid which was neutralized withsaturated NaHCO₃ solution (850 mL), after addition of water (250 mL) toobtain homogeneous, this aqueous layer was extracted with EtOAc (1×750mL, 2×500 mL). Combined EtOAc layers were filtered through small pad ofsilica gel (sand-SiO₂-sand in sintered funnel), dried (Na₂SO₄) andevaporated to obtain 3-amino-2-cyano-5-methylpyridine (60 g) as yellowsolid in 76% yield including ˜10% corresponding amide.

To the crude 3-amino-2-cyano-5-methylpyridine (containing ˜10%carboxamide) (49 g) was added EtOAc (441 mL, 9:1 volume ratio toaniline), the resulting suspension was heated to reflux to form a cleansolution. After cooling to room temperature, the resulting crystal wascollected by filtration, washed with small amount of cold EtOAc (44 mL (1/10 the initial volume)×2), and dried in vacuo to afford the pure3-amino-2-cyano-5-methylpyridine (35 g) as pale yellow needles. Themother liquor was concentrated under reduced pressure, the resultingyellow solid was added EtOAc (136 mL) and repeated the above process toafford another 4 g of pure 3-amino-2-cyano-5-methylpyridine; totalrecovery yield 79.5%. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (1H, s), 6.90 (1H,s), 4.39 (2H, br), 2.30 (3H, s). MS (ES) M+H expect 134.0, found 134.0.

Example 397:3-(4-Chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridine-2carboxylic Acid

To 3-amino-5-methylpicolinonitrile (9.6 g, 72 mmol) in pyridine (63 mL)was added 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (19.6 g,80 mmol) in one portion and the resulting reaction mixture was stirredat 60° C. for overnight. Pyridine was removed in vacuo, added 2N HCl(100 mL), extracted with EtOAc (3×300 mL; Note: due to the amidepresence, solubility in EtOAc is low). Combined EtOAc layers were dried(Na₂SO₄), evaporated to obtain 26.3 g of crude product which contained asmall amount of bis-sulfonamide which was subjected to hydrolysis in THF(200 mL) with 2N NaOH (100 mL) at room temperature for 2 h. 2N HCl (100mL) Was added, extracted with EtOAc (1×700 mL, 1×250 mL), combined EtOAclayers were washed with saturated NaHCO₃ solution (2×250 mL), dried(Na₂SO₄) and evaporated to obtain 22 g of monosulfonamide. To thisdioxane (350 mL), water (450 mL) (Note: requires high dilution for fastreaction) was added, followed by NaOH (30 g, 0.75 mol) and stirred underreflux for 24 h. Dioxane was removed in vacuo and conc. HCl (75 mL) wasadded slowly with cooling. The resultant solid was filtered, washed withwater and dried in vacuo to afford title compound (22 g, 88% for 2steps) as light yellow solid. (M+H) Expected: 395.0; found 394.9.

Example 398:5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenyl-sulfonamido)picolinicAcid

Step 1

A dry 250 mL flask was charged with 2-bromo-5-chloro-3-nitropyridine (24g, 101 mmol), CuCN (19 g, 212 mmol) and DMF (100 mL). The resultantmixture was stirred at 110° C. for 2 h. The mixture was concentratedunder reduced pressure. Water (100 mL) was added and extracted withEtOAc (3×250 mL). The combined organic layer was washed with brine,dried (MgSO₄) and filtered. The solvent was evaporated the solvent invacuo to afford a light yellow solid (15 g) which was used directly forthe next step.

Step 2

A 250 mL round-bottom flask with a magnetic stir bar was charged withiron powder (15.6 g, 0.3 mol) in acetic acid (80 mL) and heated to 80°C. (oil bath) under N₂. To this mixture was added slowly the abovenitrocyanopyridine (10 g, 55 mmol) from step 1 in acetic acid (80 mL)via dropping funnel over 15 min. The mixture was stirred at 80° C. foranother 30 min after the addition. After cooling, the reaction mixturewas diluted with EtOAc, filtered through celite and the solventevaporated in vacuo. The residue was dissolved in EtOAc and washed with3N NaOH, brine, dried over MgSO₄, and concentrated in vacuo to afford a4:1 mixture (7.7 g) of 3-amino-2-cyano-5-chloropyridine (major) and the2-amide. The mixture was used directly for the next step: MS (ES) [M+H]⁺expected 154.0, found 154.0.

Step 3

A 100 mL round-bottom flask was charged with the above3-amino-2-cyano-5-chloropyridine mixture (7.7 g, 50 mmol),4-chloro-3-trifluoromethylbenzenesulfonyl chloride (28 g, 100 mmol), andpyridine (50 mL). The resultant solution was heated to 70° C. andstirred for 5 h. The pyridine was removed in vacuo and 80% aq. EtOH (260mL) was added, followed by NaOH (30 g, 0.75 mol). The mixture wasstirred under reflux for 12 h. The solvent was subsequently removed invacuo and ice (100 g) was added. The pH adjusted to 2-3 with conc. HCl.The resultant aqueous solution was extracted with EtOAc, washed withbrine, dried over MgSO₄, and concentrated in vacuo. The resulting lightyellow solid was recrystallized from EtOAc/hexane (1:1) to afford thedesired acid as white needles (10 g, 44% overall yield): ¹H NMR (400MHz, CDCl₃) δ 10.80 (s, 1H), 8.23 (m, 3H), 8.00 (d, 1H), 7.63 (d, 1H);MS (ES) (M+H)⁺ expected 415.0, found 415.0.

Example 399:5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid methoxy-methyl-amide

5-Chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid (15.8, 38 mmol), N,O-dimethyl hydroxylamine hydrochloride (11.1 mg,114 mmol), DIEA (41 mL, 228 mmol) methyl-m-tolyl-amine (44 mg, 0.36mmol), and BOP (69 mg, 49 mmol), were reacted according to the procedureD for the synthesis of5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-picolinicamides at 50° C. The reaction mixture was quenched with 1 (M) HCl,extracted with EtOAc, and the organic portions were washed with 1 (M)aqueous HCl, NaHCO₃ and brine. The combined organic extracts were dried(Na₂SO₄), filtered and concentrated under reduced pressure. Theresulting residue was purified by flash column chromatography to afford5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methoxy-methyl-amide: MS m/z: (M+H) 458.0.

Example 400:5-Chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid methoxy-methyl-amide

5-Chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methoxy-methyl-amide was prepared from5-Chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid as described in example 144.

Example 401:5-Chloro-3-[methoxymethyl-(4-methyl-3-trifluoromethyl-benzenesulfonyl)-amino]-pyridine-2-carboxylicAcid methoxy-methyl-amide

To a mixture of sodium hydride (164 mg, 4.10 mmol) in 5 mL of THF wasadded a mixture of5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methoxy-methyl-amide (1.50 g, 3.42 mmol) and chloromethyl methylether (0.388 mL, 5.13 mmol) in 5 mL of THF. The mixture was stirred atroom temperature overnight. After the removal of the solvents theresidue was purified by flash column (20% ethyl acetate in hexane) toafford 1.50 grams of the title compound as a white solid: (M⁺+H) expect482.0, found 482.0.

Example 402:5-Chloro-3-[methoxymethyl-(4-chloro-3-trifluoromethyl-benzenesulfonyl)-amino]-pyridine-2-carboxylicAcid methoxy-methyl-amide

To a suspension of sodium hydride (314 mg, 7.86 mmol) in 8 mL of THF wasadded a mixture of5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methoxy-methyl-amide (3.0 g, 6.55 mmol) and chloromethyl methylether (0.741 mL, 9.825 mmol) in 8 mL of THF. The mixture was stirred atroom temperature overnight. After the removal of the solvents theresidue was purified by flash column (20% ethyl acetate in hexane) toafford 2.70 grams of the title compound as a white solid. (M+H)⁺ expect502.0, found 502.0.

Example 403: 3-Amino-pyridine-2-carboxylic Acid Methyl Ester

400 mg (2.9 mmol) of 3-amino-pyridine-2-carboxylic acid was dissolved in3 mL of methanol. To this solution 1.6 mL of 2M(trimethylsilyl)diazomethane solution in diethyl ether was addeddropwise at 0° C., followed by stirring of the mixture for 2 h at r.t.The solution was diluted with ethyl acetate and washed with aqueoussodium bicarbonate solution. Flash chromatography afforded the esterproduct. LC-MSD, m/z for C₇H₈N₂O₂ [M+H]+=153.0; HPLC retention time: 0.2min.

Example 404:3-(4-Chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicAcid

Prepared from 0.60 g (2.17 mmol) of4-chloro-3-trifluoromethyl-benzenesulfonyl chloride and 0.30 g (1.97mmol) of 3-amino-pyridine-2-carboxylic acid methyl ester in 3 mLpyridine using procedure x. The solvent was switched to THF, followed bythe addition of 1M aqueous LiOH and the mixture stirred for 1 h. The pHof the mixture was adjusted to neutral and the product was extractedwith ethyl acetate. LC-MSD, m/z for C₁₃H₈ClF₃N₂O₄S [M+H]+=380.9, 383.0;HPLC retention time: 1.8 min.

Example 405:3-[(4-Chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicAcid methoxy-methyl-amide

Prepared from 1.05 g (2.48 mmol) of3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylicacid methoxy-methyl-amide, 1.71 g of potassium carbonate and 566 μL ofmethoxymethyl chloride in 7 mL THF using procedure x. Yield: 420 mg of awhite solid. LC-MSD, m/z for C₁₇H₁₇ClF₃N₃O₅S [M+Na]+=490.0, 491.9; HPLCretention time: 2.5 min.

Example 406:4-Chloro-N-(2-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-5-(methoxymethyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1

To a solution of the bromopyridine (132 mg, 0.28 mmol) in carbontetrachloride (4 mL) was added N-bromosuccinimide (60 mg, 1.2 equiv.),followed by 2,2′-azobisisobutyronitrile (AIBN, 4.6 mg, 0.1 equiv.). Thereaction mixture was heated at 60° C. overnight. After cooling down toroom temperature, excessive carbon tetrachloride was removed and theresidue was purified by flash chromatography on silica gel (33%EtOAc/hexanes). The desired product was obtained as a white solid (107mg, 70%). MS: (M+H)/z=551.

Step 2

The product obtained from step 1 above (51 mg, 0.093 mmol) was dissolvedin 3 mL of methanol. To the resultant solution was added sodiummethoxide (10 mg, 2.0 equiv.). The reaction mixture was heated at 50° C.overnight. After cooling down to room temperature, the reaction wasquenched with saturated ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (33% EtOAc/hexanes). The desiredproduct was obtained as a white solid (42 mg, 90%). MS: (M+H)/z=503.

Example 407:3-(4-Chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridine-2-carboxylicAcid methoxy-methyl-amide

10.49 g (26.6 mmol) of3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridine-2-carboxylicacid was reacted with 5.40 g (33.2 mmol) of N,N′-carbonyldiimidazole in40 mL of refluxing THF for 3 h. The temperature was lowered to 50° C.,2.86 g (29.3 mmol) of O,N-dimethyl-hydroxylamine hydrochloride was addedand the reaction was stirred overnight at 50° C. Half of the solvent wasremoved under reduced pressure and the reaction mixture was diluted with200 mL of cold water. The solids were filtered off, washed with 100 mLof water and dried to give 9.8 g (84%) of the product as a tan powder.

Example 408:3-[(4-Chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-5-methyl-pyridine-2-carboxylicAcid methoxy-methyl-amide

Prepared from 223 mg (0.51 mmol) of3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridine-2-carboxylicacid methoxy-methyl-amide, 352 mg of potassium carbonate and 116 μL ofmethoxymethyl chloride in 1 mL THF using procedure x. Yield: 200 mg of awhite solid. LC-MSD, m/z for C₁₈H₁₉ClF₃N₃O₅S [M+H]+=482.0, 484.0; HPLCretention time: 2.5 min.

Example 409: 7-Chloro-3H-imidazo[4,5-b]pyridine

The product was prepared following the procedure from Bioorg. Med. Chem.Lett. 2004, 3165-3168.

Example 410: 6-Iodo-9H-purine

A mixture of 6-chloro-9H-purine (684 mg, 4.46 mmol) and 6 mL of 57%hydriodic acid were stirred at 0° C. for 1.5 h. The reaction yielded 840mg of the product as a white powder. The solid was filtered off,suspended in 5 mL of water and brought to pH=8 with aqueous ammoniasolution. The suspension was cooled down to 0° C. and the solid wasfiltered off, washed with cold water and dried to give the product.

Example 411: 4-Iodo-7H-pyrrolo[2,3-d]pyrimidine

A mixture of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (673 mg, 4.41 mmol)and 7 mL of 57% hydriodic acid was stirred at room temperature for 16 h.The solid was filtered off, suspended in 5 mL of water and brought topH=8 with aqueous ammonia solution. The suspension was cooled down to 0°C. and the solid was filtered off, washed with cold water and dried togive the product to yield 970 mg of the product as a white powder. Theproduct contains about 10% of the starting material.

Example 412: 7-Iodo-3H-imidazo[4,5-b]pyridine

A mixture of 7-chloro-3H-imidazo[4,5-b]pyridine (1.47 g, 9.64 mmol) and15 mL of 57% hydriodic acid were reacted at 80° C. for 4 h. After thesolid was filtered off it was resubmitted to the reaction with 10 mL offresh 57% hydriodic acid. The reaction yielded 1.3 g of the product as ablack powder, 90% pure.

Example 413: General Procedure for N-Protection of the Iodoheterocycles

1.65 mmol of the iodoheterocycle was dissolved in 2 mL DMF and cooleddown to 0° C. To this solution 1.81 mmol of 60% sodium hydride was addedfollowed by dropwise addition of 1.81 mmol of trimethylsilylethoxymethylchloride over the period of 5 minutes. The solution was stirred at 0° C.for 0.5 h, followed by 0.5 h at r.t. To this solution 10 mL of water wasadded and the mixture was extracted twice with 10 mL of diethyl ether.The organic layers were washed with 10 mL of water, then dried overanhydrous magnesium sulfate, evaporated under reduced pressure andpurified on silica using ethyl acetate in hexanes.

Example 414: 6-Iodo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-purine

405 mg (1.65 mmol) of 6-iodo-9H-purine was dissolved in 2 mL DMF. 72 mg(1.81 mmol) of 60% sodium hydride was added followed by 320 μL (1.81mmol) of trimethylsilylethoxymethyl chloride. Yield: 343 mg of an oilyproduct.

Example 415:4-Iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine

610 mg (2.49 mmol) of 4-iodo-7H-pyrrolo[2,3-d]pyrimidine was dissolvedin 2.5 mL DMF. 110 mg (2.74 mmol) of 60% sodium hydride was addedfollowed by 480 μL (2.74 mmol) of trimethylsilylethoxymethyl chloride.Yield: 750 mg of an oily product, 90% pure.

Example 416: 4-Iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine

206 mg (0.84 mmol) of 4-iodo-7H-pyrrolo[2,3-d]pyrimidine was dissolvedin 1 mL DMF. 37 mg (0.92 mmol) of 60% sodium hydride was added followedby 58 μL (0.92 mmol) of iodomethane. The reaction was quenched by adding10 mL of water, the solid filtered off, washed with 10 mL of water, then10 mL of hexanes and dried. Yield: 142 mg of a tan powder, 90% pure.

Example 417:7-Iodo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine

850 mg (3.47 mmol) of 7-iodo-3H-imidazo[4,5-b]pyridine was dissolved in3.5 mL DMF. 153 mg (3.82 mmol) of 60% sodium hydride was added followedby 670 μL (3.82 mmol) of trimethylsilylethoxymethyl chloride. Yield: 424mg of an oily product, 90% pure.

Example 418: General Procedure for Ketones from Weinreb Amides

Step 1

Addition of the Grignard reagent:_1 mmol of the iodoheterocycle wasdissolved under nitrogen atmosphere in 4 mL THF and cooled down to −30°C. 0.50 mL of 2M solution of isopropylmagnesium chloride solution in THFwas added dropwise. The mixture was warmed up to −10° C. and stirred for10 minutes, which resulted in a complete iodine-magnesium exchange. Thesolution was then cooled down to −20° C. and 1.0 mmol of solid Weinrebamide was added. After 5 minutes the mixture was allowed to warm up tor.t. and was stirred at r.t. for 1 h. Aqueous ammonium chloride solutionwas added and the mixture was extracted with DCM. Organic layer wasevaporated under reduced pressure. Flash chromatography on silica usingethyl acetate in hexanes afforded the products.

Step 2

Deprotection: 1 mmol of the protected ketone intermediate was dissolvedin a mixture of 20 mL of methanol and 20 mL of 6N hydrochloric acid. Thesolution was heated in a sealed tube at 95° C. for 8 h, then cooled downand evaporated. The residue was dissolved in methanolic ammonia andevaporated on silica gel under reduced pressure. Flash chromatography onsilica using ethyl acetate in hexanes afforded the products as a yellowsolids. In some cases additional reverse-phase HPLC purification stepwas necessary to obtain pure products.

Example 419: General Procedure for the Preparation of Ketones fromNitriles

1 mmol of 4-iodo-7H-pyrrolo[2,3-d]pyrimidine was dissolved undernitrogen atmosphere in 2.8 mL THF and cooled down to −10° C. 0.50 mL of2M solution of phenylmagnesium chloride solution in THF was addeddropwise followed by 0.50 mL of 2M solution of isopropylmagnesiumchloride solution in THF. The mixture was warmed up to r.t. and stirredfor 1 h, which resulted in a complete iodine-magnesium exchange. Aseparate solution of 0.77 mmol of the corresponding nitrile in 1 mL THFwas prepared and 0.96 mmol of 60% sodium hydride was added to it. Thesolutions were combined and the mixture was stirred at 45° C. for 8 h.The reaction mixture was cooled down to r.t., 0.52 mL of concentratedhydrochloric acid was added and the mixture was stirred at 50° C. for0.5 h. The solids were filtered off and washed with three 10 mL portionsof THF, followed by 10 mL of diethyl ether and four portions of 1Nhydrochloric acid. The solids were taken up in the mixture of aqueoussodium bicarbonate and ethyl acetate. The organic layer was passedthrough a pad of silica gel and evaporated under reduced pressure togive the products.

Example 420:4-Chloro-N-[5-chloro-2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide

^(i)PrMgCl (3.84 mL, 7.56 mmol; 1.97M solution in THF) was added toiodopyrrolopyrimidine (0.882 g, 3.6 mmol) in THF (5 mL) at −78° C. After15 min, it was warmed to room temperature and added2,6-dimethylphenymagnesium bromide (2.4 mL, 2.4 mmol; 1.0M solution indiethyl ether). To this reaction mixture at room temperature was added asodium salt THF solution of4-chloro-2-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-N-methoxy-N-methyl-benzamide[prepared separately by adding 60% NaH (0.144 g, 3.6 mmol) in THF (5mL)] and stirred overnight. Saturated NH₄Cl solution (5 mL) was addedand extracted with EtOAc (2×50 mL). EtOAc layer was washed with brine(25 mL), dried (Na₂SO₄) and evaporated. Crude product was purified bycolumn purification (silica gel, 60% EtOAc in hexanes) followed byrecrystallization from CH₃CN to obtain title compound (1 g) as acrystalline yellow solid in 67% yield. MS (ES) M+H expected 515.0, found514.9. ¹H NMR (CDCl₃, 400 MHz): δ 10.75 (s, 1H), 9.92 (brs., 1H), 8.92(d, 1H), 8.05 (s, 1H), 7.92 (dd, 1H), 7.81 (m, 2H), 7.58 (m, 1H), 7.45(dd, 1H), 7.3 (d, 1H), 6.9 (m, 1H).

Example 421:4-Chloro-N-[2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Prepared from 248 mg (0.53 mmol) of3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid methoxy-methyl-amide, 239 mg (0.58 mmol) of 90%4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidinedissolved in 2 mL THF with 0.32 mL of 2M isopropylmagnesium chloridesolution in THF added. All of the resulting intermediate ketone was usedin the second step with 4 mL methanol and 4 mL 6N hydrochloric acidmixture to give after purification 29 mg of the final product as ayellow solid.

Example 422:4-Chloro-N-[5-chloro-2-(7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Prepared from 227 mg (0.45 mmol) of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid methoxy-methyl-amide, 129 mg (0.45 mmol) of 90%4-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with0.23 mL of 2M isopropylmagnesium chloride solution in THF added. All ofthe resulting intermediate ketone (80 mg) was used in the second stepwith 2 mL ethanol and 2 mL 6N hydrochloric acid mixture to give afterpurification 45 mg of the final product as a yellow solid.

Example 423: Preparation of4-Chloro-N-(5-(methoxymethyl)-2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1

To a solution of the bromopyridine obtained from Example 13 (step 2) (74mg, 0.15 mmol) in THF (1 mL) at 0° C. was added isopropylmagnesiumchloride (147 μL, 2.0M in THF) dropwise. After 45 minutes, a solution of7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidine-4-carbaldehyde (67 mg,0.22 mmol) in THF was added. The reaction mixture was warmed up to roomtemperature and stirred overnight. The reaction was quenched withsaturated ammonium chloride solution, and the mixture was extracted withethyl acetate. The extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel (33% EtOAc/hexanes). The desired productwas obtained as a foaming yellow solid (45 mg, 42%). MS: (M+H)/z=728.

Step 2

The product obtained from step 1 above (45 mg, 0.062 mmol) was dissolvedin 3 mL of dichloromethane. To the resultant solution was addedDess-Martin periodinane (42 mg, 1.6 equiv.) and stirred overnight atroom temperature. The reaction was quenched with 10% Na₂S₂O₃, and themixture was extracted with ethyl acetate. The extracts were washed withsaturated NaHCO₃, brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (33%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (35 mg, 78%). MS: (M+H)/z=726.

Step 3

The product obtained from step 2 above (35 mg, 0.048 mmol) was dissolvedin 4 mL of HCl-dioxane (4.0M) and 1 mL of water. The mixture was heatedat 85° C. for 30 minutes and quenched with saturated NaHCO₃. The mixturewas extracted with ethyl acetate. The extracts were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel (10% methanol/DCM). Thedesired product was obtained as a yellow solid (15 mg, 60%). MS:(M+H)/z=526.

Example 424:4-Chloro-N-[5-methyl-2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Prepared from 200 mg (0.42 mmol) of3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-5-methyl-pyridine-2-carboxylicacid methoxy-methyl-amide, 202 mg (0.50 mmol) of 90%4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidinedissolved in 2 mL THF with 0.25 mL of 2M isopropylmagnesium chloridesolution in THF added. All of the resulting intermediate ketone was usedin the second step with 2 mL methanol and 2 mL 6N hydrochloric acidmixture to give after purification 29 mg of the final product as ayellow solid.

Example 425:4-Methyl-N-[5-methyl-2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Prepared from 496 mg (1.40 mmol) ofN-(2-cyano-5-methyl-pyridin-3-yl)-4-methyl-3-trifluoromethyl-benzenesulfonamideand 70 mg (1.75 mmol) of 60% sodium hydride in 2 mL THF. The Grignardsolution was prepared from 467 mg (1.82 mmol) of 95%4-iodo-7H-pyrrolo[2,3-d]pyrimidine dissolved in 5 mL THF with 0.98 mL of2M phenylmagnesium chloride solution in THF and 0.98 mL of 2Misopropylmagnesium chloride solution in THF added. The reaction yielded340 mg of the final product as a yellow solid.

Example 426:3,4-Dichloro-N-[5-methyl-2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-pyridin-3-yl]-benzenesulfonamide

Prepared from 563 mg (1.55 mmol) of3,4-dichloro-N-(2-cyano-5-methyl-pyridin-3-yl)-benzenesulfonamide sodiumsalt, 506 mg (2.01 mmol) of 97% 4-iodo-7H-pyrrolo[2,3-d]pyrimidinedissolved in 6 mL THF with 1.16 mL of 1.8M phenylmagnesium chloridesolution in THF and 1.06 mL of 2M isopropylmagnesium chloride solutionin THF added. The reaction yielded 471 mg of the final product as ayellow solid.

Example 427: Preparation of4-Chloro-N-(5-methyl-2-(2-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1

To a suspension of NaH (60% dispersion in mineral oil, 1.62 g, 40.5mmol) in DMF (35 mL) and benzene (12 mL) was added ethyl cyanoacetate(4.7 mL, 44.2 mmol) dropwise at −10° C. After stirring for 1 hour atroom temperature, 2-bromo-1,1-diethoxyethane (5.6 mL, 0.82 equiv.) wasadded and the reaction mixture was heated at 100° C. for 2 hours. Thereaction mixture was then cooled to room temperature and filtered. Thefiltrate was condensed, and water was added. The mixture was extractedwith ether. The extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel (20% EtOAc/hexanes). The desired productwas obtained as colorless oil (5 g, 60%). MS: (M+Na)/z=252.

Step 2

Acetamidine hydrochloride (413 mg, 4.4 mmol) was added to a solution ofsodium ethoxide (594 mg, 2.0 equiv.) in ethanol (8 mL). After stirringfor half an hour at room temperature, the resultant sodium chloride wasremoved by filtration. The filtrate was added to ethyl2-cyano-4,4-diethoxybutanoate (1.0 g, 4.4 mmol) and the mixture wasrefluxed for 5 hours. Most of the solvent was removed and the remainingslurry was dissolved in ice water, and extracted with ethyl acetate. Theextracts were washed with brine, dried over MgSO₄ and concentrated invacuo. The crude material was purified by flash chromatography on silicagel (100% methanol). The desired product was obtained as a red solid(421 mg, 40%). MS: (M+H)/z=242.

Step 3

The above pyrimidine (2.0 g, 8.30 mmol) was added to a solution ofsulfuric acid (0.9 mL) in 50 mL of ethanol and refluxed for 2 hours.After cooling down to room temperature, the mixture was concentrated invacuo. The crude material (soluble in water) was used directly for thenext step. MS: (M+H)/z=150.

Step 4

A suspension of 90 mg (0.60 mmol) of the above hydroxypyrrolopyrimidinein 2 mL of phosphorous oxychloride was refluxed for 2 hours. The excessphosphorous oxychloride was removed and the residue was quenchedcarefully with ice. The mixture was extracted with ethyl acetate. Theextracts were washed with brine, dried over MgSO₄ and concentrated invacuo. The crude material was purified by flash chromatography on silicagel (10% methanol/DCM). The desired product was obtained as a colorlesssolid (86 mg, 85%). MS: (M+H)/z=168.

Step 5

The above chloropyrrolopyrimidine (40 mg, 0.24 mmol) was added to anaqueous solution of hydroiodic acid (57 wt. % in water, 1.5 mL) and themixture was heated at 35° C. overnight. After cooling down to roomtemperature, a solution of hydroxylamine was added and the mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo. The desired product was obtainedas a brown solid (50 mg, 80%). MS: (M+H)/z=260.

Step 6

To a solution of3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)-N-methoxy-N,5-dimethylpicolinamide(56 mg, 0.13 mmol) in THF (1 mL) at 0° C. was added NaH (60% dispersionin mineral oil, 6 mg, 1.2 equiv.). The reaction was then warmed up toroom temperature and stirred for 0.5 hour. In a separate flask wascharged the above iodopyrrolopyrimidine (40 mg, 1.2 equiv.) in 0.5 mL ofTHF. The solution was cooled to −78° C., and a solution ofisopropylmagnesium chloride in THF (2.0M, 167 μL) was added dropwise.The reaction mixture was then warmed up to room temperature and asolution of 2,6-dimethylphenyl magnesium bromide solution (1.0M, 167 μL,1.3 equiv.) in THF was added. After stirring for half an hour, themixture was added to the above Weinreb amide solution and the reactionwas stirred for an additional hour before quenching with saturatedammonium chloride solution. The mixture was extracted with ethylacetate. The extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel (33% EtOAc/hexanes). The desired productwas obtained as a yellow solid (31 mg, 40%). MS: (M+H)/z=510.

Example 428:4-Chloro-N-[5-chloro-2-(9H-purine-6-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Prepared from 256 mg (0.51 mmol) of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid methoxy-methyl-amide, 191 mg (0.51 mmol) of6-iodo-9-(2-trimethylsilanyl-ethoxymethyl)-9H-purine dissolved in 2 mLTHF with 0.25 mL of 2M isopropylmagnesium chloride solution in THFadded. All of the resulting intermediate ketone was used in the secondstep with 1 mL methanol and 1 mL 6N hydrochloric acid mixture to giveafter purification 2.05 mg of the final product as a yellow solid.

Example 429:4-Chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Prepared from 494 mg (1.00 mmol) ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamidedissolved in 2 mL THF, 1.05 mL of 2M isopropylmagnesium chloridesolution in THF. 146 mg (1.00 mmol) of1H-pyrrolo[2,3-c]pyridine-4-carbaldehyde was dissolved in 1 mL THF andtreated sequentially at r.t. with 44 mg (1.1 mmol) of 60% sodium hydrideand 177 uL (1 mmol) of trimethylsilylethoxymethyl chloride prior toaddition to the Grignard reagent solution. Yield: 40 mg of theintermediate alcohol. All of it was used in the second step with 74 mgof Dess-Martin periodinane dissolved in 1 mL of DCM. The 31 mg of theresulting protected ketone was subjected to step 3 in 2 mL methanol and2 mL 6N hydrochloric acid mixture at 100° C. to give after purification17 mg of the final product as a yellow solid. LC-MSD, m/z forC₂₀H₁₁Cl₂F₃N₄O₃S [M+H]+=514.9, 516.9; HPLC retention time: 2.3 min.

Example 430:3,4-Dichloro-N-[5-methyl-2-(1H-pyrrolo[2,3-c]pyridine-4-carbonyl)-pyridin-3-yl]-benzenesulfonamide

Prepared from 204 mg (0.464 mmol) ofN-(2-bromo-5-methyl-pyridin-3-yl)-3,4-dichloro-N-methoxymethyl-benzenesulfonamidedissolved in 1 mL THF, 0.49 mL of 2M isopropylmagnesium chloridesolution in THF. 75 mg (0.510 mmol) of1H-pyrrolo[2,3-c]pyridine-4-carbaldehyde was dissolved in 1 mL THF andtreated at r.t. with 22 mg (0.557 mmol) of 60% sodium hydride prior toaddition to the Grignard reagent solution. All of the intermediatealcohol was used in the second step with 300 mg of Dess-Martinperiodinane dissolved in 2 mL of DCM. The resulting protected ketone wassubjected to step 3 in 6 mL methanol and 6 mL 6N hydrochloric acidmixture at 90° C. to give after purification 22 mg of the final productas a yellow solid. LC-MSD, m/z for C₂₀H₁₄Cl₂N₄O₃S [M+H]+=460.9, 462.9;HPLC retention time: 2.3 min.

Example 431:4-Chloro-N-[5-chloro-2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

Prepared from 259 mg (0.52 mmol) of5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylicacid methoxy-methyl-amide, 213 mg (0.52 mmol) of 90%4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidinedissolved in 2 mL THF with 0.26 mL of 2M isopropylmagnesium chloridesolution in THF added. All of the resulting intermediate ketone was usedin the second step with 2 mL methanol and 2 mL 6N hydrochloric acidmixture to give after purification 40 mg of the final product as ayellow solid.

Example 432: Synthesis of4-chloro-N-{5-chloro-2-[hydroxy-(1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-phenyl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution of1-(tert-butyl-dimethyl-silanyl)-4-iodo-1H-pyrrolo[2,3-b]pyridine (97.4mg, 0.27 mmol) in THF (2 mL) under nitrogen atmosphere at 0° C. wasadded drop wise isopropylmagnisum chloride (2M solution in THF, 0.27 mL,0.54 mmol). The mixture was then stirred for 30 min at 0° C. followed bythe addition of a solution of4-chloro-N-(5-chloro-2-formyl-phenyl)-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (120 mg, 0.27 mmol) in THF (2 mL) at 0° C. The mixture wasstirred at room temperature for overnight, quenched with saturatedaqueous NH₄Cl solution (5 mL) and extracted with EtOAc (2×25 mL).Combined organic layers were washed with saturated aqueous NH₄Clsolution (25 mL), brine (25 mL), dried (anhydrous Na₂SO₄) andconcentrated under reduced pressure. Obtained residue was columnpurified (SiO₂, 30% EtOAc-hexanes) to obtain4-chloro-N-{5-chloro-2-[hydroxy-(1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-phenyl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(88 mg) in 48% yield. ESMS m/z (relative intensity): 674 (M+H)+(100).

Example 433: Synthesis of4-chloro-N-[5-chloro-2-(1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-phenyl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

To a solution of4-chloro-N-{5-chloro-2-[hydroxy-(1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-methyl]-phenyl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(88 mg, 0.13 mmol) in CH₂Cl₂ (3 mL) was added Dess-Martin periodinane(99.8 mg, 0.235 mmol) and stirred for 5 h at room temperature. 10%Na₂S₂O₃ (3 mL) and saturated aqueous NaHCO₃ solution (3 mL) was addedand stirred for 30 min. Aqueous layer was separated and extracted withEtOAc (2×25 mL). Combined organic layers were washed with saturatedaqueous NaHCO₃ solution (20 mL), brine (20 mL), dried (anhydrousNa₂SO₄), concentrated and column purified (SiO₂, 30% EtOAc-hexanes) toobtain4-chloro-N-[5-chloro-2-(1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-phenyl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(80 mg) in 92% yield. ESMS m/z (relative intensity): 672 (M+H)+(100).

Example 434: Synthesis of4-chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide

A mixture of4-chloro-N-[5-chloro-2-(1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-phenyl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(20 mg, 0.029 mmol) in 4N HCl in dioxane (2 mL) and water (0.5 mL) wasstirred at 70° C. for overnight. MeOH (0.5 mL) was added and furtherstirred at the same temperature for 30 min. Then reaction mixture wascooled to room temperature, evaporated to dryness and treated withsaturated aqueous NaHCO₃ solution till pH 7-8. The mixture was extractedwith EtOAc (2×25 mL), dried (anhydrous Na₂SO₄) and concentrated. Theobtained residue was purified by HPLC to afford4-chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-phenyl]-3-trifluoromethyl-benzenesulfonamidein 60% yield. ESMS m/z (relative intensity): 514 (M+H)⁺ (100).

Example 435:4-Chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-isopropyl-benzenesulfonamide

Prepared from 25 mg (0.092 mmol) of(3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanoneand 81 mg (0.32 mmol) of 4-chloro-3-iso-propyl-benzenesulfonyl chloridein 0.2 mL pyridine using procedure x. After the sulfonylation wascomplete, 3 mL methanol, 0.5 mL water and 44 mg sodium hydroxide wereused. Yield: 18 mg of a yellow solid. LC-MSD, m/z for C₂₂H₁₈C₁₂N₄O₃S[M+H]+=489.0, 491.0.

Example 436:N-[5-Chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-4-cyano-3-trifluoromethyl-benzenesulfonamide

Prepared from 40 mg (0.15 mmol) of(3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanoneand 137 mg (0.51 mmol) of 4-cyano-3-trifluoromethyl-benzenesulfonylchloride in 0.3 mL pyridine using procedure x. After the sulfonylationwas complete, 3 mL methanol, 0.5 mL water and 71 mg sodium hydroxidewere used. Yield: 10 mg of a yellow solid. LC-MSD, m/z forC₂₁H₁₂ClF₃N₅O₃S [M+H]+=505.9, 507.9.

Example 437:3-Chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-4-methyl-benzenesulfonamide

Prepared from 20 mg (0.075 mmol) of(3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanoneand 58 mg (0.25 mmol) of 3-chloro-4-methyl-benzenesulfonyl chloride in0.15 mL pyridine using procedure x. After the sulfonylation wascomplete, 3 mL methanol, 0.5 mL water and 35 mg sodium hydroxide wereused. Yield: 9 mg of a yellow solid. LC-MSD, m/z for C₂₀H₁₄C₁₂N₄O₃S[M+H]+=460.9, 462.9.

Example 438:N-[5-Chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-fluoro-4-methyl-benzenesulfonamide

Prepared from 18 mg (0.066 mmol) of(3-amino-5-chloro-pyridin-2-yl)-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methanoneand 48 mg (0.25 mmol) of 3-fluoro-4-methyl-benzenesulfonyl chloride in0.10 mL pyridine using procedure x. After the sulfonylation wascomplete, 2 mL methanol, 0.5 mL water and 32 mg sodium hydroxide wereused. Yield: 20 mg of a yellow solid. LC-MSD, m/z for C₂₀H₁₄ClFN₄O₃S[M+H]+=445.0, 447.0.

Example 439:3-tert-Butyl-4-chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-benzenesulfonamide

Prepared from 160 mg (0.332 mmol) ofN-(2-bromo-5-chloro-pyridin-3-yl)-3-tert-butyl-4-chloro-N-methoxymethyl-benzenesulfonamidedissolved in 1 mL THF, 0.35 mL of 2M isopropylmagnesium chloridesolution in THF and 95 mg (0.365 mmol) of1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde.Yield: 180 mg of the intermediate alcohol. All of it was used in thesecond step with 180 mg of Dess-Martin periodinane dissolved in 5 mL ofDCM. 55 mg of the resulting protected ketone was subjected to step 3 in2 mL methanol and 2 mL 6N hydrochloric acid mixture to give afterpurification 20 mg of the final product as a yellow solid. LC-MSD, m/zfor C₂₃H₂₀Cl₂N₄O₃S [M+H]+=503.0, 505.0.

Example 440:4-Chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-(1-hydroxy-1-methyl-ethyl)-benzenesulfonamide

Prepared from 147 mg (0.30 mmol) ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1-hydroxy-1-methyl-ethyl)-N-methoxymethyl-benzenesulfonamidedissolved in 1 mL THF (in this case the solution was cooled down to −40°C. prior to the addition of the Grignard reagent), 0.47 mL of 2Misopropylmagnesium chloride solution in THF and 86 mg (0.33 mmol) of1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde.Yield: 132 mg of the intermediate alcohol. All of it was used in thesecond step with 210 mg of Dess-Martin periodinane dissolved in 2 mL ofDCM. 96 mg of the resulting protected ketone was subjected to step 3 in4 mL methanol and 4 mL 6N hydrochloric acid mixture to give afterpurification 37 mg of the final product as a yellow solid. LC-MSD, m/zfor C₂₂H₁₈Cl₂N₄O₄S [M+H]+=505.0, 507.0.

Example 441:4-Chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-(1,1-difluoro-ethyl)-benzenesulfonamide

Prepared from 162 mg (0.331 mmol) ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-(1,1-difluoro-ethyl)-N-methoxymethyl-benzenesulfonamidedissolved in 1 mL THF, 0.35 mL of 2M isopropylmagnesium chloridesolution in THF and 95 mg (0.364 mmol) of1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde.All of the intermediate alcohol was used in the second step with 350 mgof Dess-Martin periodinane dissolved in 2 mL of DCM. 95 mg of theresulting protected ketone was subjected to step 3 in 3 mL methanol and3 mL 6N hydrochloric acid mixture to give after purification 50 mg ofthe final product as a yellow solid. LC-MSD, m/z for C₂₁H₁₄C₁₂F₂N₄O₃S[M+H]+=510.9, 512.9.

Example 442:4-Chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-ethyl-benzenesulfonamide

Prepared from 186 mg (0.41 mmol) ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-ethyl-N-methoxymethyl-benzenesulfonamidedissolved in 1 mL THF, 0.43 mL of 2M isopropylmagnesium chloridesolution in THF and 117 mg (0.45 mmol) of1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde.Yield: 152 mg of the intermediate alcohol. All of it was used in thesecond step with 255 mg of Dess-Martin periodinane dissolved in 1 mL ofDCM. The resulting protected ketone was subjected to step 3 in 3 mLmethanol and 3 mL 6N hydrochloric acid mixture to give afterpurification 50 mg of the final product as a yellow solid. LC-MSD, m/zfor C₂₁H₁₆C₁₂N₄O₃S [M+H]+=474.9, 476.9; HPLC retention time: 2.8 min.

Example 443:N-[5-Chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-4-ethyl-3-trifluoromethyl-benzenesulfonamide

A solution/suspension made of 97 mg (0.22 mmol) ofN-(2-bromo-5-chloro-pyridin-3-yl)-4-ethyl-3-trifluoromethyl-benzenesulfonamide,140 mg (0.87 mmol) of 1H-pyrrolo[2,3-b]pyridine-4-boronic acid (mixturewith its neopentyl glycolate ester and 1H-pyrrolo[2,3-b]pyridine), 240mg (1.74 mmol) of potassium carbonate and 15 mg (0.022 mmol) ofbis(triphenylphosphine)dichloropalladium(II) in 1 mL of anisole wasstirred at 150° C. under 10 atm pressure of carbon monoxide for 2 h.After cooling down and decompression the mixture was introduced onto aflash column and eluted with 50-100% ethyl acetate in hexanes. Fractionscontaining the product were repurified on reverse-phase HPLC and freebased to give 3.5 mg of the product as a yellow solid. LC-MSD, m/z forC₂₂H₁₆ClF₃N₄O₃S [M+H]+=509.0, 511.0.

Example 444:N-(2-{[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-hydroxy-methyl}-5-chloro-6-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethylbenzenesulfonamide

To a solution ofN-(2-Bromo-5-chloro-6-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(152.7 mg, 0.3 mmol) in 2 ml of THF under nitrogen atmosphere at 0° C.was added via syringe 2.0M isopropyl magnesium chloride (0.36 ml, 0.72mmol). The reaction mixture was stirred for about 45 minutes and1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde(54 mg, 0.21 mmol) was added and the resultant mixture was stirred for30 minutes at 0° C. and then 2 hours at room temperature. The mixturewas quenched with saturated ammonium chloride and extracted with ethylacetate. The organic layer was separated and washed with water twice anddried. Concentration of this mixture afforded the crude product (210 mg)which was used in the next step without any further purification. MS(ES) (M+H) expect 689, found 688.9.

Example 445:N-{2-[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl]-5-chloro-6-methyl-pyridin-3-yl}-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide

A mixture ofN-(2-{[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-hydroxy-methyl}-5-chloro-6-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethylbenzenesulfonamide(from above step), Dess-Martin periodinane (424 mg, 1.0 mmol) in 3 ml ofDCM was stirred at room temperature for overnight. The mixture wasdirectly purified by flash chromatography (25% ethyl acetate in hexane)to afford the desired title compound. MS (ES) (M⁺+H) expect 687, found686.9.

Example 446:4-Chloro-N-[5-chloro-6-methyl-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

A mixture ofN-{2-[1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbonyl]-5-chloro-6-methyl-pyridin-3-yl}-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(from above step) in 2 ml of 4M HCl and 2 ml of dioxane was stirred at90° C. for 2 hours. The mixture was concentrated and the residue wasdiluted with ethyl acetate, this organic layer was washed with saturatedsodium bicarbonate and followed by brine and then dried over sodiumsulfate. After filtration and concentration the residue was purified bypreparative TLC to afford the title compound. 1H NMR: (CD₃OD, ppm): 8.15(d, 1H), 7.98 (s, 1H), 7.84 (m, 1H), 7.53 (m, 1H), 7.40 (d, 1H), 7.26(d, 1H), 7.07 (d, 1H), 6.23 (d, 1H), 2.47 (s, 3H); MS (ES) (M⁺+H) expect529, found 528.9.

Example 447:4-Chloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-methyl-benzenesulfonamide

The title compound was synthesized according to procedures outlinedabove using1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehydeMS (M+H): 461.0.

Example 448:4-Chloro-N-[5-methyl-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized according to procedures outlinedabove using1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde.MS (M+H): 495.0.

Example 449:N-[5-Chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide

The title compound was synthesized according to procedures outlinedusing1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde.MS (M+H): 481.0.

Example 450:3,4-Dichloro-N-[5-chloro-2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-pyridin-3-yl]-benzenesulfonamide

The title compound was synthesized according to procedures outlinedabove using1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde.MS (M+H): 480.9.

Example 451:3,4-Dichloro-N-[2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-5-trifluoromethyl-pyridin-3-yl]-benzenesulfonamide

The title compound was synthesized according to procedures outlinedabove using1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde.MS (M+H): 514.9.

Example 452: Preparation of 4-(5-Chloro-3-(4-methyl-3-(trifluoromethyl)phenylsulfonamido)picolinoyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridine7-oxide

To a stirred solution of the azaindole obtained from Example 1 (13 mg,0.025 mmol) in chloroform (5 mL) was added peracetic acid (20 μL, 32% wtin acetic acid). The reaction mixture was stirred for 2 days at roomtemperature and quenched with saturated NaHCO₃. The mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (80% EtOAc/hexanes). The desiredproduct was obtained as a yellow solid (11 mg, 80%). ¹HNMR: (400 MHz,CDCl₃) δ 8.16 (s, 2H), 8.11 (s, 1H), 8.00 (s, 1H), 7.96 (dd, J=8.4, 2.0Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.34 (d, J=3.6 Hz, 1H), 6.25 (d, J=3.2Hz, 1H), 3.61 (s, 3H), 2.53 (s, 3H); MS: (M+H)/z=541.

Example 453: Preparation of4-Chloro-N-(2-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-5-methylpyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1

To a solution of the bromopyridine (74 mg, 0.16 mmol) in THF (1 mL) at0° C. was added isopropylmagnesium chloride (156 μL, 2.0M in THF)dropwise. After 45 minutes, a solution of the aldehyde obtained fromstep 5, example 1 above (54 mg, 0.16 mmol) in THF was added. Thereaction mixture was warmed up to room temperature and stirredovernight. The reaction was quenched with saturated ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The extractswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (25%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (62 mg, 55%). MS: (M+H)/z=727.

Step 2

The product obtained from step 1 above (45 mg, 0.062 mmol) was dissolvedin 2 mL of dichloromethane. To the resultant solution was addedDess-Martin periodinane (42 mg, 1.6 equiv.) and stirred overnight atroom temperature. The reaction was quenched with 10% Na₂S₂O₃, and themixture was extracted with ethyl acetate. The extracts were washed withsaturated NaHCO₃, brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (20%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (28 mg, 62%). MS: (M+H)/z=725.

Step 3

The product obtained from step 2 above (28 mg, 0.039 mmol) was dissolvedin 4 mL of HCl-dioxane (4.0M) and 1 mL of water. The mixture was heatedat 85° C. for 30 minutes and quenched with saturated NaHCO₃. The mixturewas extracted with ethyl acetate. The extracts were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel (80% EtOAc/hexanes). Thedesired product was obtained as a yellow solid (12 mg, 59%). MS:(M+H)/z=525.

Example 454: Preparation4-(3-(4-Chloro-3-(trifluoromethyl)phenylsulfonamido)-5-methylpicolinoyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridine7-oxide

To a stirred solution of the azaindole from Example 4 (20 mg, 0.038mmol) in chloroform (5 mL) was added peracetic acid (31 μL, 32% wt inacetic acid). The reaction mixture was stirred for 2 days at roomtemperature and quenched with saturated NaHCO₃. The mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (80% EtOAc/hexanes). The desiredproduct was obtained as a yellow solid (15 mg, 73%). MS: (M+H)/z=541.

Example 455: Preparation ofN-(2-(5-Methoxy-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-5-methylpyridin-3-yl)-4-methyl-3-(trifluoromethyl)benzenesulfonamide

Step 1

To a solution of the bromopyridine (68 mg, 0.15 mmol) in THF (1 mL) at0° C. was added isopropylmagnesium chloride (150 μL, 2.0M in THF)dropwise. After 45 minutes, a solution of the aldehyde obtained fromstep 5, Example 1 above (50 mg, 0.15 mmol) in THF was added. Thereaction mixture was warmed up to room temperature and stirredovernight. The reaction was quenched with saturated ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The extractswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (33%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (60 mg, 57%). MS: (M+H)/z=707.

Step 2

The product obtained from step 1 above (56 mg, 0.079 mmol) was dissolvedin 2 mL of dichloromethane. To the resultant solution was addedDess-Martin periodinane (54 mg, 1.6 equiv.) and stirred overnight atroom temperature. The reaction was quenched with 10% Na₂S₂O₃, and themixture was extracted with ethyl acetate. The extracts were washed withsaturated NaHCO₃, brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (20%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (40 mg, 71%). MS: (M+H)/z=705.

Step 3

The product obtained from step 2 above (41 mg, 0.057 mmol) was dissolvedin 4 mL of HCl-dioxane (4.0M) and 1 mL of water. The mixture was heatedat 85° C. for 30 minutes and quenched with saturated NaHCO₃. The mixturewas extracted with ethyl acetate. The extracts were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel (80% EtOAc/hexanes). Thedesired product was obtained as a yellow solid (20 mg, 68%). MS:(M+H)/z=505.

Example 456: Preparation of5-Methoxy-4-(5-methyl-3-(4-methyl-3-(trifluoromethyl)phenylsulfonamido)picolinoyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide

To a stirred solution of the azaindole from Example 5 (20 mg, 0.040mmol) in chloroform (5 mL) was added peracetic acid (28 μL, 32% wt inacetic acid). The reaction mixture was stirred for 2 days at roomtemperature and quenched with saturated NaHCO₃. The mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (80% EtOAc/hexanes). The desiredproduct was obtained as a yellow solid (12 mg, 58%). MS: (M+H)/z=521.

Example 457: Preparation of4-Chloro-N-(2-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1

To a solution of the bromopyridine (152 mg, 0.33 mmol) in THF (1 mL) at0° C. was added isopropylmagnesium chloride (330 μL, 2.0M in THF)dropwise. After 45 minutes, a solution of the aldehyde obtained fromstep 5, Example 1 above (110 mg, 0.33 mmol) in THF was added. Thereaction mixture was warmed up to room temperature and stirredovernight. The reaction was quenched with saturated ammonium chloridesolution, and the mixture was extracted with ethyl acetate. The extractswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (33%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (120 mg, 51%). MS: (M+H)/z=713.

Step 2

The product obtained from step 1 above (120 mg, 0.17 mmol) was dissolvedin 2 mL of dichloromethane. To the resultant solution was addedDess-Martin periodinane (114 mg, 1.6 equiv.) and stirred overnight atroom temperature. The reaction was quenched with 10% Na₂S₂O₃, and themixture was extracted with ethyl acetate. The extracts were washed withsaturated NaHCO₃, brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (33%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (100 mg, 83%). MS: (M+H)/z=711.

Step 3

The product obtained from step 2 above (50 mg, 0.070 mmol) was dissolvedin 4 mL of HCl-dioxane (4.0M) and 1 mL of water. The mixture was heatedat 85° C. for 30 minutes and quenched with saturated NaHCO₃. The mixturewas extracted with ethyl acetate. The extracts were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel (80% EtOAc/hexanes). Thedesired product was obtained as a yellow solid (20 mg, 56%). MS:(M+H)/z=511.

Example 458: Preparation of4-(3-(4-Chloro-3-(trifluoromethyl)phenylsulfonamido)picolinoyl)-5-methoxy-1H-pyrrolo[2,3-b]pyridine 7-oxide

To a stirred solution of the azaindole from Example 7 (32 mg, 0.063mmol) in chloroform (5 mL) was added peracetic acid (45 μL, 32% wt inacetic acid). The reaction mixture was stirred for 2 days at roomtemperature and quenched with saturated NaHCO₃. The mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (80% EtOAc/hexanes). The desiredproduct was obtained as a yellow solid (20 mg, 61%). MS: (M+H)/z=527.

Example 459: Preparation of4-Chloro-N-(5-methyl-2-(5-propoxy-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1

A 100 mL round-bottom flask was charged with4-chloro-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine (1.2 g, 3.9mmol), THF (20 mL) and the mixture was cooled to −78° C. Asec-butyllithium solution (1.4M in cyclohexane, 4.2 mL, 1.5 equiv.) wasadded dropwise and after 30 minutes, titanium isopropoxide (2.2 mL, 2.0equiv.) was added rapidly. The reaction mixture was warmed up to 0° C.for 15 minutes and then cooled to −78° C. and a solution oftert-butylhydrogen peroxide in decane (5.5M, 0.71 mL, 1.0 equiv.) wasadded. After 1 hour, the reaction mixture was quenched with saturatedammonium chloride solution. The mixture was allowed to reach roomtemperature and then extracted with ethyl acetate. The combined organiclayers were washed with brine and dried over MgSO₄. Solvent was removedand the crude material was purified by flash chromatography on silicagel (10% EtOAc/hexanes). The desired product was obtained as a colorlessliquid (760 mg, 60%). MS: (M+H)/z=325.

Step 2

To a solution of triphenylphosphine (288 mg, 1.10 mmol) in 2 mL of THFwas added diisopropyl azodicarboxylate (DIAD, 213 μL, 1.1 equiv.) atroom temperature. After 10 minutes, isopropanol (84 μL, 1.1 equiv.) wasadded. After another 5 minutes, the product obtained from step 1 above(324 mg, 1.00 mmol) was added in one portion. The reaction mixture wasstirred for half an hour before it was quenched with saturated ammoniumchloride solution. The mixture was extracted with ethyl acetate. Theextracts were washed with brine, dried over MgSO₄ and concentrated invacuo. The crude material was purified by flash chromatography on silicagel (10% EtOAc/hexanes). The desired product was obtained as a solid(320 mg, 87%). MS: (M+H)/z=367.

Step 3

The product obtained from step 2 above (110 mg, 0.30 mmol) dissolved in3 mL of THF. To this mixture was added TBAF (1.0M in THF, 0.60 mL, 2.0equiv.). The reaction mixture was stirred overnight at room temperature,quenched with saturated ammonium chloride solution, and extracted withethyl acetate. The extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel (50% EtOAc/hexanes). The desired productwas obtained as a solid (55 mg, 87%). MS: (M+H)/z=211.

Step 4

The product obtained from step 3 above (100 mg, 0.48 mmol) was dissolvedin 4 mL of acetonitrile. Then NaI (357 mg, 5 equiv.) was added followedby acetyl chloride (71 μL, 2.1 equiv.). The reaction mixture was allowedto stir at 80° C. for 1 hour, and then excessive acetonitrile wasremoved in vacuo. A mixture of 10% K₂CO₃ (10 mL) and 10% sodiumbisulfite (10 mL) was added to the residue and the mixture was extractedwith ethyl acetate and washed with brine. The combined organic layer wasdried over MgSO₄ and concentrated in vacuo to give the crude product. Toa solution of this crude product in THF (3 mL) was added 1M NaOH (0.5mL). The mixture was stirred for 1 hour at room temperature and quenchedwith saturated ammonium chloride solution. The mixture was extractedwith ethyl acetate, and the extracts were washed with brine, dried overMgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (50% EtOAc/hexanes). The desiredproduct was obtained as a white solid (122 mg, 85%). MS: (M+H)/z=303.

Step 5

The product obtained from step 4 above (150 mg, 0.50 mmol) was dissolvedin 4 mL of anhydrous DMF. Then NaH (24 mg, 60% dispersion in mineraloil, 1.2 equiv.) was added. After 30 minutes, triisopropylsilyl chloride(116 μL, 1.1 equiv.) was added and the reaction mixture was stirredovernight at room temperature. The reaction was quenched with saturatedammonium chloride solution, and the mixture was extracted with ethylacetate. The extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel (10% EtOAc/hexanes). The desired productwas obtained as colorless oil (205 mg, 90%). MS: (M+H)/z=459.

Step 6

The product obtained from step 5 above (210 mg, 0.46 mmol) was dissolvedin 3 mL of anhydrous THF and cooled to 0° C. Then isopropylmagnesiumchloride (460 μL, 2.0M in THF) was added. After 45 minutes, anhydrousDMF (1 mL) was added and the reaction mixture was warmed up to roomtemperature and stirred overnight. The reaction was quenched withsaturated ammonium chloride solution, and the mixture was extracted withethyl acetate. The extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel (5% EtOAc/hexanes). The desired product wasobtained as a pale yellow solid (88 mg, 53%). MS: (M+H)/z=361.

Step 7

To a solution of the bromopyridine (116 mg, 0.24 mmol) in THF (1 mL) at0° C. was added isopropylmagnesium chloride (250 μL, 2.0M in THF)dropwise. After 45 minutes, a solution of the product obtained from step6 above (88 mg, 0.24 mmol) in THF was added. The reaction mixture waswarmed up to room temperature and stirred overnight. The reaction wasquenched with saturated ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (20% EtOAc/hexanes). The desiredproduct was obtained as a foaming yellow solid (112 mg, 61%). MS:(M+H)/z=755.

Step 8

The product obtained from step 7 above (95 mg, 0.13 mmol) was dissolvedin 3 mL of dichloromethane. To the resultant solution was addedDess-Martin periodinane (85 mg, 1.6 equiv.) and stirred overnight atroom temperature. The reaction was quenched with 10% Na₂S₂O₃, and themixture was extracted with ethyl acetate. The extracts were washed withsaturated NaHCO₃, brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (20%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (71 mg, 75%). MS: (M+H)/z=753.

Step 9

The product obtained from step 8 above (100 mg, 0.13 mmol) was dissolvedin 4 mL of HCl-dioxane (4.0M) and 1 mL of water. The mixture was heatedat 85° C. for 30 minutes and quenched with saturated NaHCO₃. The mixturewas extracted with ethyl acetate. The extracts were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel (80% EtOAc/hexanes). Thedesired product was obtained as a yellow solid (40 mg, 55%). MS:(M+H)/z=553.

Example 460: Preparation of4-(3-(4-Chloro-3-(trifluoromethyl)phenylsulfonamido)-5-methylpicolinoyl)-5-propoxy-1H-pyrrolo[2,3-b]pyridine7-oxide

To a stirred solution of the azaindole from Example 9 (15 mg, 0.027mmol) in chloroform (5 mL) was added peracetic acid (20 μL, 32% wt inacetic acid). The reaction mixture was stirred for 2 days at roomtemperature and quenched with saturated NaHCO₃. The mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (80% EtOAc/hexanes). The desiredproduct was obtained as a yellow solid (11 mg, 70%). MS: (M+H)/z=569.

Example 461: Preparation of4-Chloro-N-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1

A 100 mL round-bottom flask was charged with4-chloro-1-triisopropylsilanyl-1H-pyrrolo [2,3-b] pyridine (308 mg, 1.0mmol), THF (5 mL) and the mixture was cooled to −78° C. Asec-butyllithium solution (1.4M in cyclohexane, 1.6 mL, 2.2 equiv.) wasadded dropwise and after 30 minutes, a solution of hexachloroethane (592mg, 2.5 equiv.) in 4 mL of THF was added rapidly. The reaction mixturewas then stirred for another 25 minutes at −78° C. and quenched withsaturated ammonium chloride solution. The mixture was allowed to reachroom temperature and then extracted with ethyl acetate. The combinedorganic layers were washed with brine and dried over MgSO₄. Solvent wasremoved and the crude material was purified by flash chromatography onsilica gel (10% EtOAc/hexanes). The desired product was obtained as ayellow solid (171 mg, 50%). MS: (M+H)/z=343.

Step 2

The product obtained from step 1 above (342 mg, 1.0 mmol) dissolved in 3mL of THF. To this mixture was added TBAF (1.0M in THF, 2.0 mL, 2.0equiv.). The reaction mixture was stirred overnight at room temperature,quenched with saturated ammonium chloride solution, and extracted withethyl acetate. The extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel (50% EtOAc/hexanes). The desired productwas obtained as a solid (167 mg, 90%). MS: (M+H)/z=187.

Step 3

The product obtained from step 2 above (105 mg, 0.56 mmol) was dissolvedin 4 mL of acetonitrile. Then NaI (423 mg, 5 equiv.) was added followedby acetyl chloride (84 μL, 2.1 equiv.). The reaction mixture was allowedto stir at 80° C. for 1 hour, and then excessive acetonitrile wasremoved in vacuo. A mixture of 10% K₂CO₃ (10 mL) and 10% sodiumbisulfite (10 mL) was added to the residue and the mixture was extractedwith ethyl acetate and washed with brine. The combined organic layer wasdried over MgSO₄ and concentrated in vacuo to give the crude product. Toa solution of this crude product in THF (3 mL) was added 1M NaOH (0.5mL). The mixture was stirred for 1 hour at room temperature and quenchedwith saturated ammonium chloride solution. The mixture was extractedwith ethyl acetate, and the extracts were washed with brine, dried overMgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (50% EtOAc/hexanes). The desiredproduct was obtained as a white solid (118 mg, 75%). MS: (M+H)/z=279.

Step 4

The product obtained from step 3 above (92 mg, 0.33 mmol) was dissolvedin 4 mL of anhydrous DMF. Then NaH (16 mg, 60% dispersion in mineraloil, 1.2 equiv.) was added. After 30 minutes, triisopropylsilyl chloride(77 μL, 1.1 equiv.) was added and the reaction mixture was stirredovernight at room temperature. The reaction was quenched with saturatedammonium chloride solution, and the mixture was extracted with ethylacetate. The extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel (10% EtOAc/hexanes). The desired productwas obtained as colorless oil (129 mg, 90%). MS: (M+H)/z=435.

Step 5

The product obtained from step 4 above (150 mg, 0.35 mmol) was dissolvedin 2 mL of anhydrous THF and cooled to 0° C. Then isopropylmagnesiumchloride (340 μL, 2.0M in THF) was added. After 45 minutes, anhydrousDMF (1 mL) was added and the reaction mixture was warmed up to roomtemperature and stirred overnight. The reaction was quenched withsaturated ammonium chloride solution, and the mixture was extracted withethyl acetate. The extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel (5% EtOAc/hexanes). The desired product wasobtained as a pale yellow solid (70 mg, 60%). MS: (M+H)/z=337.

Step 6

To a solution of xxx (151 mg, 0.33 mmol) in THF (1 mL) at 0° C. wasadded isopropylmagnesium chloride (330 μL, 2.0M in THF) dropwise. After45 minutes, a solution of the product obtained from step 5 above (110mg, 0.33 mmol) in THF was added. The reaction mixture was warmed up toroom temperature and stirred overnight. The reaction was quenched withsaturated ammonium chloride solution, and the mixture was extracted withethyl acetate. The extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel (20% EtOAc/hexanes). The desired productwas obtained as a foaming yellow solid (129 mg, 55%). MS: (M+H)/z=717.

Step 7

The product obtained from step 6 above (142 mg, 0.20 mmol) was dissolvedin 3 mL of dichloromethane. To the resultant solution was addedDess-Martin periodinane (135 mg, 1.6 equiv.) and stirred overnight atroom temperature. The reaction was quenched with 10% Na₂S₂O₃, and themixture was extracted with ethyl acetate. The extracts were washed withsaturated NaHCO₃, brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (20%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (99 mg, 70%). MS: (M+H)/z=715.

Step 8

The product obtained from step 7 above (50 mg, 0.070 mmol) was dissolvedin 4 mL of HCl-dioxane (4.0M) and 1 mL of water. The mixture was heatedat 85° C. for 30 minutes and quenched with saturated NaHCO₃. The mixturewas extracted with ethyl acetate. The extracts were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel (80% EtOAc/hexanes). Thedesired product was obtained as a yellow solid (20 mg, 56%). MS:(M+H)/z=515.

Example 462: Preparation of 5-Chloro-4-(3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinoyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide

To a stirred solution of the azaindole from Example 11 (21 mg, 0.041mmol) in chloroform (5 mL) was added peracetic acid (29 μL, 32% wt inacetic acid). The reaction mixture was stirred for 2 days at roomtemperature and quenched with saturated NaHCO₃. The mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (80% EtOAc/hexanes). The desiredproduct was obtained as a yellow solid (15 mg, 70%). MS: (M+H)/z=531.

Example 463: Preparation of4-Chloro-N-(2-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-5-(methoxymethyl)pyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

Step 1

To a solution of the bromopyridine (132 mg, 0.28 mmol) in carbontetrachloride (4 mL) was added N-bromosuccinimide (60 mg, 1.2 equiv.),followed by 2,2′-azobisisobutyronitrile (AIBN, 4.6 mg, 0.1 equiv.). Thereaction mixture was heated at 60° C. overnight. After cooling down toroom temperature, excessive carbon tetrachloride was removed and theresidue was purified by flash chromatography on silica gel (33%EtOAc/hexanes). The desired product was obtained as a white solid (107mg, 70%). MS: (M+H)/z=551.

Step 2

The product obtained from step 1 above (51 mg, 0.093 mmol) was dissolvedin 3 mL of methanol. To the resultant solution was added sodiummethoxide (10 mg, 2.0 equiv.). The reaction mixture was heated at 50° C.overnight. After cooling down to room temperature, the reaction wasquenched with saturated ammonium chloride solution, and the mixture wasextracted with ethyl acetate. The extracts were washed with brine, driedover MgSO₄ and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel (33% EtOAc/hexanes). The desiredproduct was obtained as a white solid (42 mg, 90%). MS: (M+H)/z=503.

Step 3

To a solution of the bromopyridine obtained from step 2 (60 mg, 0.12mmol) in THF (1 mL) at 0° C. was added isopropylmagnesium chloride (120μL, 2.0M in THF) dropwise. After 45 minutes, a solution of the aldehydeobtained from Example 1 (step 5) above (40 mg, 0.12 mmol) in THF wasadded. The reaction mixture was warmed up to room temperature andstirred overnight. The reaction was quenched with saturated ammoniumchloride solution, and the mixture was extracted with ethyl acetate. Theextracts were washed with brine, dried over MgSO₄ and concentrated invacuo. The crude material was purified by flash chromatography on silicagel (33% EtOAc/hexanes). The desired product was obtained as a foamingyellow solid (45 mg, 50%). MS: (M+H)/z=757.

Step 4

The product obtained from step 3 above (25 mg, 0.032 mmol) was dissolvedin 3 mL of dichloromethane. To the resultant solution was addedDess-Martin periodinane (22 mg, 1.6 equiv.) and stirred overnight atroom temperature. The reaction was quenched with 10% Na₂S₂O₃, and themixture was extracted with ethyl acetate. The extracts were washed withsaturated NaHCO₃, brine, dried over MgSO₄ and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel (33%EtOAc/hexanes). The desired product was obtained as a foaming yellowsolid (18 mg, 70%). MS: (M+H)/z=755.

Step 5

The product obtained from step 4 above (10 mg, 0.013 mmol) was dissolvedin 4 mL of HCl-dioxane (4.0M) and 1 mL of water. The mixture was heatedat 85° C. for 30 minutes and quenched with saturated NaHCO₃. The mixturewas extracted with ethyl acetate. The extracts were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel (80% EtOAc/hexanes). Thedesired product was obtained as a yellow solid (4.4 mg, 70%). MS:(M+H)/z=555.

Measuring Efficacy of Chemokine Modulators

In Vitro Assays

A variety of assays can be used to evaluate the compounds providedherein, including signaling assays, migration assays, ligand bindingassays, and other assays of cellular response. Chemokine receptorsignaling assays can be used to measure the ability of a compound, suchas a potential CCR2 antagonist, to block CCR2 ligand- (e.g.MCP-1)-induced signaling or a potential CCR9 antagonist, to block CCR9ligand- (e.g. TECK)-induced signaling. A migration assay can be used tomeasure the ability of a compound of interest, such as a possiblechemokine antagonist, to block chemokine-mediated cell migration invitro. The latter is believed to resemble chemokine-induced cellmigration in vivo. A ligand binding assay can be used to measure theability of a compound, such as a potential CCR2 antagonist, to block theinteraction of MCP-1 with its receptor or a potential CCR9 antagonist,to block the interaction of TECK with its receptor.

In a suitable assay, a chemokine protein (whether isolated orrecombinant) is used which has at least one property, activity, orfunctional characteristic of a mammalian chemokine protein. The propertycan be a binding property (to, for example, a ligand or inhibitor), asignaling activity (e.g., activation of a mammalian G protein, inductionof rapid and transient increase in the concentration of cytosolic freecalcium ion), cellular response function (e.g., stimulation ofchemotaxis or inflammatory mediator release by leukocytes), and thelike.

The assay can be a cell-based assay that utilizes cells stably ortransiently transfected with a vector or expression cassette having anucleic acid sequence that encodes the chemokine receptor. Cell linesnaturally expressing the chemokine can also be used. The cells aremaintained under conditions appropriate for expression of the receptorand are contacted with a putative agent under conditions appropriate forbinding to occur. Binding can be detected using standard techniques. Forexample, the extent of binding can be determined relative to a suitablecontrol (for example, relative to background in the absence of aputative agent, or relative to a known ligand). Optionally, a cellularfraction, such as a membrane fraction, containing the receptor can beused in lieu of whole cells.

Detection of binding or complex formation can be detected directly orindirectly. For example, the putative agent can be labeled with asuitable label (e.g., fluorescent label, chemiluminescent label, isotopelabel, enzyme label, and the like) and binding can be determined bydetection of the label. Specific and/or competitive binding can beassessed by competition or displacement studies, using unlabeled agentor a ligand (e.g., MCP-1 or TECK) as a competitor.

Binding inhibition assays can be used to evaluate the present compounds.In these assays, the compounds are evaluated as inhibitors of ligandbinding using, for example, MCP-1 or TECK. In one embodiment, the CCR2receptor is contacted with a ligand such as MCP-1 and a measure ofligand binding is made. The receptor is then contacted with a test agentin the presence of a ligand (e.g., MCP-1) and a second measurement ofbinding is made. In another embodiment, the CCR9 receptor is contactedwith a ligand such as TECK and a measure of ligand binding is made. Thereceptor is then contacted with a test agent in the presence of a ligand(e.g., TECK) and a second measurement of binding is made. A reduction inthe extent of ligand binding is indicative of inhibition of binding bythe test agent. The binding inhibition assays can be carried out usingwhole cells which express the chemokine, or a membrane fraction fromcells which express the chemokine.

The binding of a G protein coupled receptor by, for example, an agonist,can result in a signaling event by the receptor. Accordingly, signalingassays can also be used to evaluate the compounds of the presentinvention and induction of signaling function by an agent can bemonitored using any suitable method. For example, G protein activity,such as hydrolysis of GTP to GDP, or later signaling events triggered byreceptor binding can be assayed by known methods (see, for example,PCT/US97/15915; Neote et al., Cell, 72:415425 (1993); Van Riper et al.,J. Exp. Med., 177:851-856 (1993) and Dahinden et al., J. Exp. Med.,179:751-756 (1994)).

Chemotaxis assays can also be used to assess receptor function andevaluate the compounds provided herein. These assays are based on thefunctional migration of cells in vitro or in vivo induced by an agent,and can be used to assess the binding and/or effect on chemotaxis ofligands, inhibitors, or agonists. A variety of chemotaxis assays areknown in the art, and any suitable assay can be used to evaluate thecompounds of the present invention. Examples of suitable assays includethose described in PCT/US97/15915; Springer et al., WO 94/20142; Bermanet al., Immunol. Invest., 17:625-677 (1988); and Kavanaugh et al., J.Immunol., 146:4149-4156 (1991)).

Calcium signaling assays measure calcium concentration over time,preferably before and after receptor binding. These assays can be usedto quantify the generation of a receptor-signaling mediator, Ca⁺⁺,following receptor binding (or absence thereof). These assays are usefulin determining the ability of a compound, such as those of the presentinvention, to generate the receptor signaling mediator by binding to areceptor of interest. Also, these assays are useful in determining theability of a compound, such as those of the present invention, toinhibit generation of the receptor signaling mediator by interferingwith binding between a receptor of interest and a ligand.

In calcium signaling assays used to determine the ability of a compoundto interfere with binding between a chemokine receptor and a knownchemokine ligand, chemokine receptor-expressing cells (CCR2-expressingcells such as THP-1 cells or CCR9-expressing cells such as T cell lineMOLT-4 cells) are first incubated with a compound of interest, such as apotential chemokine antagonist, at increasing concentrations. The cellnumber can be from 10⁵ to 5×10⁵ cells per well in a 96-well microtiterplate. The concentration of the compound being tested may range from 0to 100 μM. After a period of incubation (which can range from 5 to 60minutes), the treated cells are placed in a Fluorometric Imaging PlateReader (FLIPR®) (available from Molecular Devices Corp., Sunnyvale,Calif.) according to the manufacturer's instruction. The FLIPR® systemis well known to those skilled in the art as a standard method ofperforming assays. The cells are then stimulated with an appropriateamount of the chemokine ligand (MCP-1 for CCR2 or TECK for CCR9) at5-100 nM final concentration, and the signal of intracellular calciumincrease (also called calcium flux) is recorded. The efficacy of acompound as an inhibitor of binding between the chemokine and the ligandcan be calculated as an IC₅₀ (the concentration needed to cause 50%inhibition in signaling) or IC₉₀ (at 90% inhibition).

In vitro cell migration assays can be performed (but are not limited tothis format) using the 96-well microchamber (called ChemoTX™). TheChemoTX™ system is well known to those skilled in the art as a type ofchemotactic/cell migration instrument. In this assay, CCR2-expressingcells (such as THP-1) or CCR9-expressing cells (such as MOLT-4) arefirst incubated with a compound of interest, such as a possible CCR2 orCCR9 antagonist, respectively, at increasing concentrations. Typically,fifty thousand cells per well are used, but the amount can range from10³-10⁶ cells per well. The chemokine ligand (for example, CCR2 ligandMCP-1, typically at 0.1 nM (but can range from 5-100 nM); or CCR9 ligandTECK, typically at 50 nM (but can range from 5-100 nM)), is placed atthe lower chamber and the migration apparatus is assembled. Twentymicroliters of test compound-treated cells are then placed onto themembrane. Migration is allowed to take place at 37° C. for a period oftime, typically 1.5 hours for CCR2 or 2.5 hours for CCR9. At the end ofthe incubation, the number of cells that migrated across the membraneinto the lower chamber is then quantified. The efficacy of a compound asan inhibitor of chemokine-mediated cell migration is calculated as anIC₅₀ (the concentration needed to reduce cell migration by 50%) or IC₉₀(for 90% inhibition).

In Vivo Efficacy Models for Human IBD

T cell infiltration into the small intestine and colon have been linkedto the pathogenesis of human inflammatory bowel diseases which includeCoeliac disease, Crohn's disease and ulcerative colitis. Blockingtrafficking of relevant T cell populations to the intestine is believedto be an effective approach to treat human IBD. CCR9 is expressed ongut-homing T cells in peripheral blood, elevated in patients with smallbowel inflammation such as Crohn's disease and Coeliac disease. CCR9ligand TECK is expressed in the small intestine. It is thus believedthat this ligand-receptor pair plays a role in IBD development bymediating migration of T cells to the intestine. Several animal modelsexist and can be used for evaluating compounds of interest, such aspotential CCR9 antagonists, for an ability to affect such T cellmigration and/or condition or disease, which might allow efficacypredictions of antagonists in humans.

Animal Models with Pathology Similar to Human Ulcerative Colitis

A murine model described by Panwala and coworkers (Panwala et al., JImmunol., 161(10):5733-44 (1998)) involves genetic deletion of themurine multi-drug resistant gene (MDR). MDR knockout mice (MDR−/−) aresusceptible to developing a severe, spontaneous intestinal inflammationwhen maintained under specific pathogen-free facility conditions. Theintestinal inflammation seen in MDR−/− mice has a pathology similar tothat of human inflammatory bowel disease (IBD) and is defined by Th1type T cells infiltration into the lamina propria of the largeintestine.

Another murine model was described by Davidson et al., J. Exp. Med.,184(1):241-51(1986). In this model, the murine IL-10 gene was deletedand mice rendered deficient in the production of interleukin 10(IL-10−/−). These mice develop a chronic inflammatory bowel disease(IBD) that predominates in the colon and shares histopathologicalfeatures with human IBD.

Another murine model for IBD has been described by Powrie et al., IntImmunol., 5(11):1461-71 (1993), in which a subset of CD4+ T cells(called CD45RB(high)) from immunocompetent mice are purified andadoptively transferred into immunodeficient mice (such as C.B-17 scidmice). The animal restored with the CD45RBhighCD4+ T cell populationdeveloped a lethal wasting disease with severe mononuclear cellinfiltrates in the colon, pathologically similar with human IBD.

Murine Models with Pathology Similar to Human Crohn's Disease

The TNF ARE(−/−) model. The role of TNF in Crohn's disease in human hasbeen demonstrated more recently by success of treatment using anti-TNFalpha antibody by Targan et al., N. Engl. J. Med., 337(15):1029-35(1997). Mice with aberrant production of TNF-alpha due to geneticalteration in the TNF gene (ARE−/−) develop Crohn's-like inflammatorybowel diseases (see Kontoyiannis et al., Immunity, 10(3):387-98 (1999)).

The SAMP/yit model. This is model described by Kosiewicz et al., J.Clin. Invest., 107(6):695-702 (2001). The mouse strain, SAMP/Yit,spontaneously develops a chronic inflammation localized to the terminalileum. The resulting ileitis is characterized by massive infiltration ofactivated T lymphocytes into the lamina propria, and bears a remarkableresemblance to human Crohn's disease.

Examples of In Vitro Assays

Reagents

THP-1 cells and MOLT-4 cells were obtained from the American TypeCulture Collection (Manassas, Va.) and cultured in RPMI tissue culturemedium supplemented with 10% fetal calf serum (FCS) in a humidified 5%CO₂ incubator at 37° C. Recombinant human chemokine proteins MCP-1 andTECK were obtained from R&D Systems (Minneapolis, Minn.). ¹²⁵I-labeledMCP-1 protein was obtained from Amersham (Piscataway, N.J.). ChemoTX®chemotaxis microchambers were purchased from Neuro Probe (Gaithersburg,Md.). CyQUANT® cell proliferation kits were purchased from MolecularProbes (Eugene, Oreg.). Calcium indicator dye Fluo-4 AM was purchasedfrom Molecular Devices (Mountain View, Calif.).

Conventional Migration Assay

Conventional migration assay was used to determine the efficacy ofpotential receptor antagonists in blocking migration mediated throughchemokines (such as CCR2 or CCR9). This assay was routinely performedusing the ChemoTX® microchamber system with a 5-μm pore-sizedpolycarbonate membrane. To begin such an assay, chemokine expressingcells (such as THP-1 cells for CCR2 assay or MOLT-4 cells for CCR9assay) were harvested by centrifugation of cell suspension at 1000 RPMon a GS-6R Beckman centrifuge. The cell pellet was resuspended inchemotaxis buffer (HBSS with 0.1% BSA) at 10×10⁶ cells/mL for CCR2 assay(5×10⁶ cells/mL for CCR9 assay). Test compounds at desiredconcentrations were prepared from 10 mM stock solutions by serialdilutions in chemotaxis buffer. An equal volume of cells and compoundswere mixed and incubated at room temperature for 15 minutes. Afterwards,20 μL of the mixture was transferred onto the porous membrane of amigration microchamber, with 29 μL of chemokine ligand (0.1 nM chemokineMCP-1 protein for CCR2 assay or 50 nm chemokine TECK protein for CCR9assay) placed at the lower chamber. Following an incubation at 37° C.(90-minute for CCR2; 150-minute for CCR9), during which cells migratedagainst the chemokine gradient, the assay was terminated by removing thecell drops from atop the filter. To quantify cells migrated across themembrane, 5 μL of 7× CyQUANT® solution was added to each well in thelower chamber, and the fluorescence signal measured on a SpectrafluorPlus fluorescence plate reader (TECAN, Durham, N.C.). The degree ofinhibition was determined by comparing migration signals betweencompound-treated and untreated cells. IC₅₀ calculation was furtherperformed by non-linear squares regression analysis using Graphpad Prism(Graphpad Software, San Diego, Calif.).

BiRAM Assay

The primary screen to identify chemokine antagonists was carried outusing BiRAM assay (WO 02101350, US2004023286), which detects potentialhits by their ability to activate cell migration under inhibitorychemokine concentration. To begin such an assay, chemokine expressingcells (such as THP-1 cells for CCR2 assay or MOLT-4 cells for CCR9assay) were harvested by centrifugation of cell suspension at 1000 RPMon a GS-6R Beckman centrifuge. The cell pellet was resuspended inchemotaxis buffer (HBSS/0.1% BSA) at 10×10⁶ cells/mL for CCR2 assay(5×10⁶ cells/mL for CCR9 assay). Twenty-five microliters of cells wasmixed with an equal volume of a test compound diluted to 20 μM in thesame buffer. Twenty microliters of the mixture was transferred onto thefilter in the upper chemotaxis chamber, with 29 μL of chemokine solutioncontaining chemokine ligand (100 nM chemokine MCP-1 and MIP-1α proteinfor CCR2 assay or 500 nm chemokine TECK protein for CCR9 assay) wasplaced in the lower chamber. Following an incubation at 37° C.(90-minute for CCR2; 150-minute for CCR9), the assay was terminated byremoving the cell drops from atop the filter. To quantify cells migratedacross the membrane, 5 μL of 7× CyQUANT® solution was added to each wellin the lower chamber, and the fluorescence signal measured on aSpectrafluor Plus fluorescence plate reader (TECAN, Durham, N.C.).

For selection of potential hits, the level of migration activation wascalculated as a RAM index—the ratio between the signal of a particularwell and the median signal of the whole plate. Compounds with a RAMindex of greater than 1.5 for CCR2 assay (1.8 for CCR9 assay) wereregarded as RAM positive, and were selected for IC₅₀ determinations inconventional functional assays.

Calcium Flux Assay

Calcium flux assay measures an increase in intracellular calciumfollowing ligand-induced receptor activation. In the screen of chemokineantagonists, it was used as a secondary assay carried out on a FLIPR®machine (Molecular Devices, Mountain View, Calif.). To begin an assay,chemokine expressing cells (such as THP-1 cells for CCR2 assay or MOLT-4cells for CCR9 assay) were harvested by centrifugation of cellsuspension, and resuspended to 1.5×10⁶ cells/mL in HBSS (with 1% fetalcalf serum). Cells were then labeled with a calcium indicator dye Fluo-4AM for 45 minutes at 37° C. with gentle shaking. Following incubation,cells were pelletted, washed once with HBSS and resuspended in the samebuffer at a density of 1.6×10⁶ cells/mL. One hundred microliters oflabeled cells were mixed with 10 μL of test compound at the appropriateconcentrations on an assay plate. Chemokine protein (MCP-1 at a finalconcentration of 0.1 nM for CCR2 assay or TECK at a final concentrationof 25 nM for CCR9 assay) to activate the receptor. The degree ofinhibition was determined by comparing calcium signals betweencompound-treated and untreated cells. IC₅₀ calculations were furtherperformed by non-linear squares regression analysis using Graphpad Prism(Graphpad Software, San Diego, Calif.).

Ligand Binding Assay

Ligand binding assay was used to determine the ability of potential CCR2antagonists to block the interaction between CCR2 and its ligand MCP-1.CCR2 expressing THP-1 cells were centrifuged and resuspended in assaybuffer (20 mM HEPES pH 7.1, 140 mM NaCl, 1 mM CaCl₂, 5 mM MgCl₂, andwith 0.2% bovine serum albumin) to a concentration of 2.2×10⁵ cells/mL.Binding assays were set up as follows. First, 0.09 mL of cells (1×10⁵THP-1 cells/well) was added to the assay plates containing thecompounds, giving a final concentration of ˜2-10 μM each compound forscreening (or part of a dose response for compound IC₅₀ determinations).Then 0.09 mL of ¹²⁵I labeled MCP-1 (obtained from Amersham; Piscataway,N.J.) diluted in assay buffer to a final concentration of ˜50 pM,yielding ˜30,000 cpm per well, was added, the plates sealed andincubated for approximately 3 hours at 4° C. on a shaker platform.Reactions were aspirated onto GF/B glass filters pre-soaked in 0.3%polyethyleneimine (PEI) solution, on a vacuum cell harvester (PackardInstruments; Meriden, Conn.). Scintillation fluid (50 μL; Microscint 20,Packard Instruments) was added to each well, the plates were sealed andradioactivity measured in a Top Count scintillation counter (PackardInstruments). Control wells containing either diluent only (for totalcounts) or excess MCP-1 (1 μg/mL, for non-specific binding) were used tocalculate the percent of total inhibition for compound. The computerprogram Prism from GraphPad, Inc. (San Diego, Ca) was used to calculateIC₅₀ values. IC₅₀ values are those concentrations required to reduce thebinding of labeled MCP-1 to the receptor by 50%.

Discovery of Chemokine Antagonists

The discovery of chemokine antagonists was carried out in two steps:First, BiRAM assay was used to screen a compound library in ahigh-throughput manner. The assay detected compounds by their ability tocause a positive migration signal under BiRAM condition. Secondly, BiRAMpositive compounds were tested to determine their IC₅₀ values using theconventional migration, calcium flux assays and ligand binding assays.

For instance, in a screen of approximately 100,000 compounds, 2000individual wells representing approximately 2% of total compounds showeda desired RAM index (greater than 1.5 for CCR2; greater than 1.8 forCCR9). These compounds were cheery-picked and retested in duplicatewells by RAM assay. A total of 156 compounds were confirmed BiRAMpositives.

Since a BiRAM positive signal indicates only the presence of a receptorantagonist and not how strongly it blocks receptor functions, the BiRAMpositive compounds were further tested for potency in conventionalmigration, calcium flux and ligand binding assays. IC₅₀ determinationson this subset discovered several compounds with an IC₅₀ less than 1 μMand that did not inhibit other chemokine receptors examined atsignificant levels.

In Vivo Efficacy

A 17-day study of type II collagen-induced arthritis is conducted toevaluate the effects of a modulator on arthritis-induced clinical ankleswelling. Rat collagen-induced arthritis is an experimental model ofpolyarthritis that has been widely used for preclinical testing ofnumerous anti-arthritic agents (see Trentham et al., J. Exp. Med.,146(3):857-868 (1977), Bendele et al., Toxicologic Pathol., 27:134-142(1999), Bendele et al., Arthritis Rheum., 42:498-506 (1999)). Thehallmarks of this model are reliable onset and progression of robust,easily measurable polyarticular inflammation, marked cartilagedestruction in association with pannus formation and mild to moderatebone resorption and periosteal bone proliferation.

Female Lewis rats (approximately 0.2 kilograms) are anesthetized withisoflurane and injected with Freund's Incomplete Adjuvant containing 2mg/mL bovine type II collagen at the base of the tail and two sites onthe back on days 0 and 6 of this 17-day study. The test modulator isdosed daily by sub-cutaneous injection from day 9 to day 17 at a dose of100 mg/kg and a volume of 1 mL/kg in the following vehicle (24.5%Cremaphore EL, 24.5% common oil, 1% Benzylalcohol and 50% Distilledwater). Caliper measurements of the ankle joint diameter are takendaily, and reducing joint swelling is taken as a measure of efficacy.

The MDR1a-knockout mice, which lack the P-glycoprotein gene,spontaneously develop colitis under specific pathogen-free condition.The pathology in these animals has been characterized as Th1-type Tcell-mediated inflammation similar to ulcerative colitis in humans.Disease normally begins to develop at around 8-10 weeks after birth.However the ages at which disease emerges and the ultimate penetrancelevel often vary considerably among different animal facilities.

In a study using the MDR1a-knockout mice, a CCR9 antagonist is evaluatedby prophylactic administration for its ability to delay disease onset.Female mice (n=34) are dosed with 50 mg/kg twice a day by subcutaneousinjections for 14 consecutive weeks starting at age 10 weeks. The studyis evaluated for IBD-associated growth retardation.

Evaluation of a Test Modulator in a Rat Model of Thioglycollate-InducedPeritoneal Inflammation

A 2-day study of thioglycollate-induced inflammation is conducted toevaluate the effects of the test modulator. The hallmarks of this modelare reliable onset and progression of robust, easily measurableinflammatory cellular infiltrate. For the induction of inflammatoryperitonitis in Lewis rats, Brewer-Thioglycollate (1.0 mL, 4% solution indistilled water) is injected intra peritoneal (i.p.). Before thisinjection, the treatment group received test modulator or vehicle andthe control group received the same volume of PBS as i.p. injection.After 2 days, a peritoneal lavage is performed with ice-cold PBScontaining 1 mM EDTA. The recovered cells are counted with a cellcounter (Coulter Counter; Coulter Pharmaceutical, Palo Alto, Calif.) andmonocytes/macrophages were identified by flow cytometry usinglight-scatter properties.

Evaluation of a Test Modulator in a Mouse Model of Bacterial Infection

A 1-day study of Streptococcus pneumoniae infection is conducted toevaluate the effects of the test modulator. The model measures bacterialinfection and spread in an animal following pulmonary infection withlive bacterial cultures, measured by inflammatory cellular infiltrate,and assessment of bacterial burden. C57/B6 mice are inoculated intranasally with LD50 400 CFU at day 0. Groups are either test modulator orvehicle control treated 1 day prior to bacterial inoculation and twicedaily throughout the study. Bacterial burden is measured at 24 hours byplating serial dilutions of homogenized lung tissue on agar plates andcounting colonies.

Pharmacologics to be Used in Conjunction with CCR2 Compounds

Pharmacological agents that can be used in conjunction with the CCR2antagonists of the current invention include those used for thetreatments of atherosclerosis, restenosis, multiple sclerosis, pulmonaryfibrosis, inflammatory bowel disease, rheumatoid arthritis,graft-versus-host disease, renal fibrosis, psoriasis, transplantationrejection, obesity, diabetes, hypercholesterolemia and cancer.

In the tables below, structures and activity are provided forrepresentative compounds described herein. Activity is provided asfollows for either or both of the chemotaxis assay and/or calciummobilization assays, described above: +, IC₅₀>1000 nM; and ++, IC₅₀<1000nM.

TABLE 1 Compounds with CCR2 activity in one of the chemotaxis, bindingor calcium mobilization assays, with IC50 < 1000 nM

TABLE 2 Compounds with CCR9 activity in one of the chemotaxis, bindingor calcium mobilization assays, with IC50 <1000 nM

It is therefore intended that the foregoing detailed description beregarded as illustrative rather than limiting, and that it be understoodthat it is the following claims, including all equivalents, that areintended to define the spirit and scope of this invention.

The invention claimed is:
 1. A method of preparing a compound of FormulaA, comprising:

(a) reacting a compound of Formula B with a Grignard reagent to producea compound of Formula C; and

(b) deprotecting the compound of Formula C to produce the compound ofFormula A, wherein Ar is selected from the group consisting ofsubstituted or unsubstituted C₆₋₁₀ aryl and substituted or unsubstituted5- to 10-membered heteroaryl; Y⁶ is halogen or substituted orunsubstituted C₁₋₈ alkyl; R is a protecting group; R¹⁰⁰ is selected fromthe group consisting of hydrogen, substituted or unsubstituted C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, substituted or unsubstituted C₆₋₁₀aryl, substituted or unsubstituted 5- to 10-membered heteroaryl andsubstituted or unsubstituted 3- to 10-membered heterocycle; and R⁶⁷ isindependently selected from the group consisting of hydrogen, halogen,substituted or unsubstituted C₁₋₈ alkyl, substituted or unsubstitutedC₂₋₈ alkenyl, substituted or unsubstituted C₂₋₈ alkynyl, —CN, ═O, —NO₂,—OR⁶⁸, —OC(O)R⁶⁸, —CO₂R⁶⁸, —C(O)R⁶⁸, —C(O)NR⁶⁹R⁶⁸, —OC(O)NR⁶⁹R⁶⁸,—NR⁷⁰C(O)R⁶⁸, —NR⁷⁰C(O)NR⁶⁹R⁶⁸, —NR⁶⁹R⁶⁸, —NR⁷⁰CO₂R⁶⁸, —SR⁶⁸, —S(O)R⁶⁸,—S(O)₂R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸, —NR⁷⁰S(O)₂R⁶⁸, substituted or unsubstitutedC₆₋₁₀ aryl, substituted or unsubstituted 5- to 10-membered heteroaryland substituted or unsubstituted 3- to 10-membered heterocyclyl; R⁶⁸,R⁶⁹, and R⁷⁰ are independently selected from the group consisting ofhydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, and heteroaryl;or R⁶⁹ and R⁶⁸ or R⁷⁰ and R⁶⁸, together with the atom(s) to which theyare attached, form an substituted or unsubstituted 5-, 6-, or 7-memberedring.
 2. The method of claim 1, wherein Y⁶ is unsubstituted C₁₋₈ alkyl.3. The method of claim 1, wherein R⁶⁷ is hydrogen.
 4. The method ofclaim 1, wherein R¹⁰⁰ is hydrogen.
 5. The method of claim 1, wherein Aris substituted or unsubstituted C₆₋₁₀ aryl.
 6. The method of claim 1,wherein the compound of Formula A is


7. The method of claim 1, wherein the Grignard reagent is formed byreacting an iodoheterocycle with an alkyl- or aryl-magnesium chloride ina solvent.
 8. The method of claim 7, wherein the alkyl-magnesiumchloride is isopropylmagnesium chloride.
 9. The method of claim 7,wherein the iodoheterocycle is a protected or unprotected4-iodo-1H-pyrrolo[2,3-b]pyridine.
 10. The method of claim 7, whereiniodoheterocycle is1-(tert-butyl-dimethyl-silanyl)-4-iodo-1H-pyrrolo[2,3-b]pyridine. 11.The method of claim 7, wherein the solvent is tetrahydrofuran.
 12. Themethod of claim 1, wherein the compound of Formula C is deprotected inthe presence of an acid.
 13. The method of claim 12, wherein the acid ishydrochloric acid.
 14. A method of preparing a compound of Formula A,comprising:

reacting a compound of Formula D with Grignard reagent to produce acompound of Formula A; and

wherein Ar is selected from the group consisting of substituted orunsubstituted C₆₋₁₀ aryl and substituted or unsubstituted 5- to10-membered heteroaryl; Y⁶ is halogen or substituted or unsubstitutedC₁₋₈ alkyl; R¹⁰⁰ is selected from the group consisting of hydrogen,substituted or unsubstituted C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,substituted or unsubstituted C₆₋₁₀ aryl, substituted or unsubstituted 5-to 10-membered heteroaryl and substituted or unsubstituted 3- to10-membered heterocycle; and R⁶⁷ is independently selected from thegroup consisting of hydrogen, halogen, substituted or unsubstituted C₁₋₈alkyl, substituted or unsubstituted C₂₋₈ alkenyl, substituted orunsubstituted C₂₋₈ alkynyl, —CN, ═O, —NO₂, —OR⁶⁸, —OC(O)R⁶⁸, —CO₂R⁶⁸,—C(O)R⁶⁸, —C(O)NR⁶⁹R⁶⁸, —OC(O)NR⁶⁹R⁶⁸, —NR⁷⁰C(O)R⁶⁸, —NR⁷⁰C(O)NR⁶⁹R⁶⁸,—NR⁶⁹R⁶⁸, —NR⁷⁰CO₂R⁶⁸, —SR⁶⁸, —S(O)R⁶⁸, —S(O)₂R⁶⁸, —S(O)₂NR⁶⁹R⁶⁸,—NR⁷⁰S(O)₂R⁶⁸, substituted or unsubstituted C₆₋₁₀ aryl, substituted orunsubstituted 5- to 10-membered heteroaryl and substituted orunsubstituted 3- to 10-membered heterocyclyl; R⁶⁸, R⁶⁹, and R⁷⁰ areindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, aryl, and heteroaryl; or R⁶⁹ and R⁶⁸or R⁷⁰ and R⁶⁸, together with the atom(s) to which they are attached,form an substituted or unsubstituted 5-, 6-, or 7-membered ring.
 15. Themethod of claim 14, wherein Y⁶ is unsubstituted C₁₋₈ alkyl.
 16. Themethod of claim 14, wherein R⁶⁷ is hydrogen.
 17. The method of claim 14,wherein R¹⁰⁰ is hydrogen.
 18. The method of claim 14, wherein Ar issubstituted or unsubstituted C₆₋₁₀ aryl.
 19. The method of claim 14,wherein the compound of Formula A is


20. The method of claim 14, wherein the Grignard reagent is formed byreacting an iodoheterocycle with an alkyl- or aryl-magnesium chloride ina solvent.